Note: this is the fifth article in a series about heartburn and GERD. If you haven’t done so already, you’ll want to read Part I, Part II, Part III, and Part IVa before reading this article.
In the last article, we discussed the first two of four primary consequences of taking acid stopping drugs:
- Bacterial overgrowth
- Impaired nutrient absorption
In this article we’ll cover the remaining two consequences:
- Decreased resistance to infection
- Increased risk of cancer and other diseases
Our first line of defense
The mouth, esophagus and intestines are home to between 400-1,000 species of bacteria. However, a healthy stomach is normally almost completely sterile. Why? Because stomach acid kills bacteria.
In fact, that’s one of it’s most important roles: to provide a two-way barrier that protects the stomach from pathogenic bacteria. First, stomach acid prevents harmful bacteria that may be present in the food or liquid we consume or the air we breathe from entering the intestine. At the same time, stomach acid also prevents normal bacteria from the intestines to move into the stomach and esophagus, where they could cause problems.
The low pH (high acid) environment of the stomach is one of the major non-specific defense mechanisms of the body. When the pH of the stomach is 3 or lower, the normal between-meal “resting” level, bacteria don’t last more than fifteen minutes. But as the pH rises to 5 or more, many bacterial species can avoid the acid treatment and begin to thrive.
Unfortunately, this is exactly what happens when you take acid stopping drugs. Both Tagamet and Zantac significantly raise the pH of the stomach from about 1 to 2 before treatment to 5.5 to 6.5 after, respectively.
Prilosec and other PPIs are even worse. Just one of these pills is capable of reducing stomach acid secretion by 90 to 95 percent for the better part of a day. Taking higher or more frequent doses of PPIs, as is often recommended, produces a state of achlorydia (virtually no stomach acid). In a study of ten healthy men aged 22 to 55 years, a 20 or 40 mg dose of Prilosec reduced stomach acid levels to near-zero.
A stomach without much acid is in many ways a perfect environment to harbor pathogenic bacteria. It’s dark, warm, moist, and full of nutrients. Most of the time these bacteria won’t kill us – at least not right away. But some of them can. People who have a gastric pH high enough to promote bacterial overgrowth are more vulnerable to serious bacterial infections.
A recent systematic review of gastric acid-suppressive drugs suggested that they do in fact increase susceptibility to infections (PDF). The author found evidence that using acid stopping drugs can increase your chances of contracting the following nasty bugs:
- Salmonella
- Campylobacter
- Cholera
- Listeria
- Giardia
- C. Difficile
Other studies have found that acid stopping drugs also increase the risk for:
Not only do acid stopping drugs increase our susceptibility to infection, they weaken our immune system’s ability to fight off infections once we have them. In vitro studies have shown that PPIs impair nuetrophil function, decrease adhesion to endothelial cells, reduce bactericidal killing of microbes, and inhibit neutrophil phagocytosis and phagolysosome acidification.
A gateway to other serious diseases
As we discussed in the first article in this series, a decline in acid secretion with age has been well documented. As recently as 1996, a British physician noted that age-related stomach acid decline is due to a loss of the cells that produce the acid. This condition is called atrophic gastritis.
In particular relevance to our discussion here, atrophic gastritis (a condition where stomach acid is very low) is associated with a wide range of serious disorders that go far beyond the stomach and esophagus. These include:
- Stomach cancer
- Allergies
- Bronchial asthma
- Depression, anxiety, mood disorders
- Pernicious anemia
- Skin diseases, including forms of acne, dermatitis, eczema, and urticaria
- Gall bladder disease (gallstones)
- Autoimmune diseases, such as Rheumatoid arthritis and Graves disease
- Irritable bowel syndrome (IBS), Crohn’s disease (CD), Ulcerative colitis (UC)
- Chronic hepatitis
- Osteoporosis
- Type 1 diabetes
And let’s not forget that low stomach acid can cause heartburn and GERD!
In the interest of keeping this article from becoming a book, I’m going to focus on just a few of the disorders on the list above.
Stomach cancer
Atrophic gastritis is a major risk factor for stomach cancer. H. pylori is the leading cause of atrophic gastritis. Acid suppressing drugs worsen H. pylori infections and increase rates of infection.
Therefore, it’s not a huge leap to suspect that acid suppressing drugs increase the risk of stomach cancer in those infected with H. pylori (which, as we saw in Part III, is one in two people).
In a recent editorial, Julie Parsonnet, M.D. of Standford University Medical School writes:
In principle, current [acid suppressing drug] therapies might be advancing the cancer clock by converting relatively benign gastric inflammation into a more destructive, premalignant process.
One way PPIs increase the risk of cancer is by inducing hypergastrinemia, a condition of above-normal secretion of the hormone gastrin. This is a potentially serious condition that has been linked to adenocarcinoma – a form of stomach cancer.
Taking a standard 20 mg daily dose of Prilosec typically results in up to a three-to-fourfold increase in gastrin levels. In people whose heartburn fails to respond to the standard dose, long-term treatment with doses as high as 40 or 60 mg has produced gastrin levels as much as tenfold above normal.
Another theory of what causes stomach cancer involves elevated concentration of nitrites in the gastric fluid. In a healthy stomach, ascorbic acid (vitamin C) removes nitrite from gastric juice by converting it to nitric oxide. However, this process is dependent upon the pH of the stomach being less than 4. As I discussed earlier in this article, most common acid stopping medications have no trouble increasing the pH of the stomach to 6 or even higher.
Therefore, it’s entirely plausible that acid stopping medications increase the risk of stomach cancer by at least two distinct mechanisms.
Gastric and duodenal ulcers
An estimated 90% of duodenal (intestinal) and 65% of gastric ulcers are caused by H. pylori. It is also recognized that the initial H. pylori infection probably only takes place when the acidity of the stomach is decreased. In a human inoculation experiment, infection could not be established unless the pH of the stomach was raised (thus lowering the acidity) by use of histamine antagonists.
By lowering stomach acid and increasing stomach pH, acid suppressing drugs increase the risk of H. pylori infection and subsequent development of duodenal or gastric ulcers.
Irritable bowel syndrome, Crohn’s disease and ulcerative colitis
Adenosine is a key mediator of inflammation in the digestive tract, and high extracellular levels of adenosine suppress and resolve chronic inflammation in both Crohn’s disease and ulcerative colitis. Chronic use of PPIs has been shown to decrease extracellular concentration of adenosine, resulting in an increase in inflammation in the digestive tract. Therefore, it is possible that long-term use of acid stopping medications may predispose people to developing serious inflammatory bowel disorders.
It has become increasingly well established that irritable bowel syndrome (IBS) is caused at least in part by small bowel bacterial overgrowth (SIBO). It is also well known that acid suppressing drugs contribute to bacterial overgrowth, as I explained in Part II and Part III. It makes perfect sense, then, that chronic use of acid suppressing drugs could contribute to the development of IBS in those that didn’t previously have it, and worsen the condition in those already affected.
Depression, anxiety and mood disorders
While there is no specific research (that I am aware of) linking acid suppressing drugs to depression or mood disorders, a basic understanding of the relationship between protein digestion and mental health suggests that there may be a connection.
During the ingestion of food stomach acid secretion triggers the release of pepsin. Pepsin is the enzyme responsible for breaking down protein into its component amino acids and peptides (two or more linked amino acids). Essential amino acids are called “essential” because we cannot manufacture them in our bodies. We must get them from food.
If pepsin is deficient, the proteins we eat won’t be broken down into these essential amino acid and peptide components. Since many of these essential amino acids, such as phenylalanine and tryptophan, play a crucial role in mental and behavioral health, low stomach acid may predispose people towards developing depression, anxiety or mood disorders.
Autoimmune diseases
Low stomach acid and consequent bacterial overgrowth cause the intestine to become permeable, allowing undigested proteins to find their way into the bloodstream. This condition is often referred to as “leaky gut syndrome”. Salzman and colleagues have shown that both transcellular and paracellular intestinal permeability are substantially increased in atrophic gastritis sufferers compared to control patients.
When undigested proteins end up in the bloodstream, they are considered as “foreign” by the immune system. The resulting immune response is similar to what happens when the body mobilizes its defenses (i.e. T cells, B cells and antibodies) to eradicate a viral or bacterial infection.
This type of immune response against proteins we eat contributes to food allergies. A similar mechanism that is not fully understood predisposes people with a leaky gut to develop more serious autoimmune disorders such as lupus, rheumatoid arthritis, type 1 diabetes, Graves disease, and inflammatory bowel disorders like Crohn’s and ulcerative colitis.
The connection between rheumatoid arthritis (RA) and low stomach acid in particular has been well established in the literature. Examining the stomach contents of 45 RA patients, Swedish researchers found that 16 (36 percent) had virtually no stomach acid. Those people who had suffered from RA the longest had the least acid. A group of Italian researchers also found that people with RA have an extremely high rate of atrophic gastritis associated with low stomach acid when compared with normal individuals.
Asthma
In the last ten years, more than four hundred scientific articles concerned with the connection between asthma and gastric acidity have been published. One of the most common features of asthma, in addition to wheezing, is gastroesophageal reflux. It is estimated that between up to 80 percent of people with asthma also have GERD. Compared with healthy people, those with asthma also have significantly more reflux episodes and more acid-induced irritation of their esophageal lining.
When acid gets into the windpipe, there is a tenfold drop in the ability of the lungs to take in and breathe out air. Physicians who are aware of this association have begun prescribing acid stopping drugs to asthma patients suffering from GERD. While these drugs may provide temporary symptomatic relief, they do not address the underlying cause of the LES dysfunction that permitted acid into the esophagus in the first place.
In fact, there is every reason to believe that acid suppressing drugs make the underlying problem (too little stomach acid and overgrowth of bacteria) worse, thus perpetuating and exacerbating the condition.
Conclusion
As we have seen in the previous articles in the series, heartburn and GERD are caused by too little – and not too much – stomach acid. Unfortunately, insufficient stomach acid is also associated with bacterial overgrowth, impaired nutrient absorption, decreased resistance to infection, and increased risk of stomach cancer, ulcers, IBS and other digestive disorders, depression and mood disorders, autoimmune disease, and asthma.
Chronic use of acid stopping medication dramatically reduces stomach acid, thus increasing the risk of all of these conditions. What’s more, acid suppressing medications not only do not address the underlying cause of heartburn and GERD, they make it worse.
Is the temporary symptom relief these drugs provide worth the risk? That’s something only you can decide. I hope the information I’ve provided here can help you make an educated decision.
In the next and final article of the series, I will present a plan for getting rid of heartburn and GERD once and for all without drugs.
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{ 18 comments… read them below or add one }
Well, I am pleased to report that after almost two weeks off PPI meds (Aciphex, after years of Nexium) I am mostly asymptomatic. A few flare-ups here and there but nothing like the disabling OMFG-kill-me-now pain I had years ago when I first went on Nexium. Thanks for the scientific ammo my brain needed to get off this stuff.
I’m aware that it may take a long time for my gizzard to recover from the PPI onslaught.
Hi Chris,
I have really enjoyed your articles. I have been on a low carb diet for a long time and have seen great results but I am not completely symptom free yet. How long is this process generally? I have not taken HCL partly because I thought is this just another pill I will have to take forever, I do take probiotics. Do you find that eventually people can stop taking HCL and not have symptoms return? I was on prilosec for seven years! I was also wondering do you find the other symptoms (asthma) that come with reflux go away once the relux is resolved?
Final article in the series is up.
Also, the entire series as well as recommendations for books and offsite articles can be found here.
Hi Amy,
I just published the article on treatment. Hopefully that will answer your questions. It can take a while for the bacterial overgrowth to rebalance. Replacing stomach acid is very important, whether you do it with HCL (preferred), bitters, lemon juice, sauerkraut or apple cider vinegar.
Some people find that they only need to take HCL for a short time, others continue to use it. It varies person to person, and depends somewhat on how long they took acid suppressing drugs and the severity of their condition.
You’ve done a very solid review of the evidence. I wish I had never taken PPIs but now I have Barrett’s esophagus, with the result that the conseqeunces of being wrong are greater than just a flare up of heartburn… There is not conclusive proof that PPIs prevent cancer in those with BE, but most evidence suggests they so. Thus, for people with BE, PPIs may not be elective.
Daniel,
Thanks for making that point. I intended to include a section called “When to seek medical help” at the end of the last article, but forgot! I’ll do it in a couple of hours. What I would have said is that if there’s structural damage to the esophagus, surgery or medication may be necessary – as you have suggested.
I think, in principal, controlling reflux should be superior than taking a PPI for cancer prevention in people with BE. That said, if reflux is recalcitrant (e.g., on account of severe hiatal hernia), skipping the PPIs may be harmful. Cancer progression in BE seems to be mediated by inflammation and associated oxidative damage. Acid supression reduces certain markers of inflammation (but not others…) and may have a role in supressing ROS formation (and may have a role in causing ROs formation…). The best evidence seems to be that the cancer progression rate used to be about 1% per year and now it is .5% per year. It could just be measurment error, but acid suppression (at minimum) doesn’t seem to hurt (much) as progression to cancer among people with BE on long-term acid suppression is about 0.3% per year according to a 2006 UK study. Turns out, antioxidants and nitrite scavengers, like vit C and vit E (and melatonin & NAC are promitting too) may do more to prevent cancer than PPIs, at least if the animal and limited human case report evidence is to be trusted.
Daniel,
The potential protective effect of PPIs needs to be weighed against the potentially neoplastic effect of insufficient stomach acid and bacterial overgrowth.
From Effect of Proton Pump Inhibitors on Vitamins and Iron, published in the American Journal of Gastroenterology last year:
“The ability of ascorbic acid to remove nitrite from gastric juice by converting it to nitric oxide is highly pH dependent. In gastric juice of pH>4 (which is easily achieved by taking PPIs), the nitrite entering the stomach in swallowed saliva remains as nitrite and causes an increase in gastric juice concentration.
The original Correa hypothesis of gastric cancer developing in patients with atrophic gastritis hypothesized a central role for the elevated gastric nitrite concentration.”
This suggests a possible mechanism by which chronic hypochlorhydria could increase the risk of gastric cancer.
There is also a known link between atrophic gastritis, in association with achlorydria or hypochlorydria, and cancer. The risk increases with the severity of the problem and the length of time a person has it. In one Danish study, people with the most severe atrophic gastritis had a four-to-sixfold increased risk of developing gastric cancer. Perhaps most importantly in the context of this discussion, it took up to seventeen years after achlorhydria was diagnosed for cancer to develop.
As you have pointed out, there’s no direct proof that PPIs increase cancer risk, and some evidence suggesting the opposite is true. However, because it can take up to twenty years for cancer to develop, and widespread, chronic use of PPIs is a relatively new phenomenon, I don’t think we can safely conclude that PPIs do not increase cancer risk.
I also think it’s important to pay attention to the physiological mechanisms involved and the circumstantial evidence, in the absence of direct clinical proof. There is no doubt that acid suppression promotes bacterial overgrowth, and that bacterial overgrowth promotes production of carcinogenic nitrosamine compounds. There is also no doubt that acid-suppressing drugs increase both the severity and progression of atrophic gastritis in people with H. pylori infection, and atrophic gastritis is a major risk factor for gastric carcinoma.
One researcher commented on these risks in 1988, before PPI use became widespread:
“Until information is available about the effects of powerful gastric secretory inhibitors on the proliferative indices and patterns of the human mucosa, the drugs must be categorized as too dangerous to use therapeutically, especially since the proposed benefits are minimal.”
It’s certainly not a cut and dry issue, and there is much conflicting evidence. Still, if there’s any way at all of controlling symptoms without PPI use I think that is the most prudent approach. I realize this will not always be possible.
Excellent points. It is a dilemma!
The vit C, nitrite thing is complicated. There was a very recent mechanistic study that in the presence of 10% fat (almost any meal), vit C actually produces more nitrites in conditions that simulate the stomach. The idea was that vit C prevents nitrite formation but causes nitric oxide (NO) to be formed which dissolves in fat and then (I think because the NO is insulated from the water-soluble vit C) forms nitrosamines… Perhaps vit E would help…
In any case, it’s not clear how much nitrites are involved in the progression to gastric cancer. This guys thesis is 2 years old but very itneresting. http://theses.gla.ac.uk/394/01/2008patersonphd.pdf
Also, h pylori (which lowers stoach acid) seems to protect against esophageal cancer in people with BE.
Daniel,
Thanks for the link. I’ll check it out – sounds very interesting.
I think we’re agreed that this is a complex issue with no clear conclusion. Thanks for your comments!
Agreed. And, thank you for this series. It is pretty damn good.
Hi Chris,
What if a person cannot start taking HCI or ACV or bitters due to too much acid, can I just low carb and slowly reduce the PPI and take yogurt and some licorice as well and lose weight of course and all the other lifestyle changes?
Gerald
Chris,
WOW! I was blown away by your article. I was up most of the night with heartburn and got online to search for answers. I take nexium 40 mg once a day and ranitidine at night. When my new insurance company cut my nexium from 2 a day to 1 a day I started taking prevacid as well. I still suffer every single day!
Three years ago I was found to be gluten and dairy (casin) intolerant. I’m off all gluten and dairy. I feel so much better as far as that goes. About a year and a half ago I found out that I have laryngopharyngeal reflux (LPR), thus starting all the medication I’m now on. I also have asthma (however that started at age 10) and osteopina.
Do you know if there is a connection between gluten intolerance, as wheat is one of the “gluten grains”, and GERD/LPR in connection with low stomach acid?
One of my sister also has LPR and is on the same medication. Gluten intolerance runs in families and my family is pretty jacked up. Thanks for the information. I will soon start to get off all the life sucking meds., I’m on.
Sincerely,
Katy
Chris,
This is the best series of articles I have seen on GERD and I have emailed links to several friends. My reflux was so bad that many nights I sat on the couch to sleep as laying down was just not an option. About a month ago, I started on the Paleo diet because it just made so much sense to me, and within one week I was sleeping flat with no discomfort, bloating or gas after meals. I am a nurse, but my focus has always been on natural medicine so I resisted acid reducing medication, but was not getting good results with several natural remedies. Your articles made me understand why my paleo diet of no grains or legumes and not too much fruit worked so well. Thanks!
Holly
Hi there,
This is very serious.
Why doesn’t the FDA come out with guidelines or cacel the permit for PPI’s?
This is such a fantastic article. I recently had an endoscopy and was informed that I have erosions in my stomach but tested negative for H. Pilori. I don’t GERD symptoms in that I have no reflux problems, but do have constant gas pains and bloating. My doctor prescribed Protonix, which I’m very hesitant to take because of everything you’ve stated. Your article deals mostly with reflux problems but does the same reasoning apply to erosions? Is there any benefit to taking Protonix to allow the erosions to heal? Thanks so much!!!
Your treatment plan works! It takes a while. I was taking Pepcid Complete, which is only 10 mg famotidine and some calcium/magnesium antacids. It worked flawlessly the two days or so I had issues. Then Johnson and Johnson decided to take it off the market. I switched to (gasp) Prilosec. Took it two weeks, doc said, no no bad stuff, stop taking. Four months of rebound acid later, I am “fixed” I tried fermented dairy. I tried manuka honey. That made it worse. So did ACV. Finally, I tried the NOW brand of enzymes and it took a couple weeks but I took them religiously. I have a few issues now and then, for example, if I spend a lot of time weeding or gardening, or simply bend over, I will get some reflux, but it is tolerable and as soon as I stand up it goes away.
I had to get a blood draw for labs so had to fast after dinner until about 2 pm the next day. All I had was black coffee. No heartburn at all that day. That was so nice to discover, that coffee is not the issue, bending over is! Ate chili for dinner last night, no reflux. Ate leftover chili for lunch, no reflux. I did not try any of the other stuff, other than the enzymes. The stuff works! I cut back from 5 after every meal to 4.