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Barrett's oesophagus, Omeprazole dosage and bile reflux: links to medical papers

This is a listing of URLs relevant to Barrett's oesophagus, Omeprazole dosage and bile reflux. The search reveals some interesting pages! But a quote from Robert A. Heinlein's short story Life-Line is relevant here:

"There are but two ways of forming an opinion in science. One is the scientific method, the other the scholastic. One can judge from experiment, or one can blindly accept authority. To the scientific mind, experimental proof is all-important, and theory is merely a convenience in description, to be junked when it no longer fits. To the academic mind, authority is everything, and facts are junked then they do not fit theory laid down by authority.

"It is this point of view - academic minds clinging like oysters to disproved theories - that has blocked every advance of knowledge in history."

Many (most?) medical papers are academic! Scientific medical papers are few. I have tried to find scientific papers...

It is also true that, because of my own experiences with PPIs, I was searching for explanations so have been looking for the bad things about PPIs. There are probably more papers proving they are good - but anyone with experience of being prescribed PPIs will know that doctors in general know they are miracle drugs.

There is a problem with almost all research papers, but particularly with those that find exactly what they set out to find. This is what an old chemistry master of mine at Sherborne School called "The Will of the Investigator" - it is extremely difficult to be impartial and there is a strong tendency for research papers to find exactly what they expect. Indeed, I could be accused of that - but in my case I found that, when I experimented, I suffered from Bile reflux. This as not what I expected. Not being in a position to do useful research myself, I set out to try and explain from published research papers whether I was unique and what was causing this bile reflux. From that I got interested in other possible deleterious side effects: conclusion - there are not many papers that are worth considering.

Alternative therapies for acid reflux

PPIs are the conventional cure, but there are other possibilities


  1. Modulation of Gastric Acid Secretion by Hypnosis. The brain is deeply involved in the feedback loop that controls acidity. This paper shows that hypnosis can affect acid secretion. It should therefore be possible, if some biofeedback system could be found, to learn to reduce acidity. Certainly it is well known that worry increases acid levels. Learning not to worry is indicated: my own experience is that with sufficient time and practise, one can significantly lower ones own acidity by willpower alone. I must write up my experiences in this sometime!
  2. Treatment of non-cardiac chest pain: a controlled trial of hypnotherapy This article concludes "Hypnotherapy appears to have use"

I have not tried hypnotherapy myself, but I have noted that, although the oesophagus is in theory insensitive to pain, reflux seems to cause much pain in a lot of people. I am lucky, I suffer little pain, yet have had reflux apparently all my life. Is this due to my relaxed attitude towards reflux? If so, hypnotherapy could be very useful to some sufferers.


Manipulation by a skilled chiropractor or osteopath is claimed to be helpful to some hiatal hernia sufferers. A Google search is informative, including a few YouTube videos. There are also self-help exercises that are claimed to help.

However it seems that, with advancing age, the phrenoesophageal ligament relaxes and allows a sliding hiatal hernia, so manipulation is only likely to have any effect in the young, where reflux tends to resolve naturally as the child ages.

However I went to a chiropractor who did the manipulation. I think it did nothing useful. But she did say that my diaphragm was tense and she manipulated my spine to relax my diaphragm. I believe this did have useful effect. This is backed up by the next alternative therapy.

Abdominal breathing

As above, my own experiences confirm the benefit of proper abdominal breathing.

Conventional antacids

Probably the most important alternative therapy to Proton Pump Inhibitors is to use the old, time proven, traditional antacids. There are so many, they deserves a separate page = Antacids.

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Barrett's oesophagus sufferers may be more prone to GERD pain than normal

I did a search of Google search which indicated that an inflamed oesophagus is more sensitive than a normal oesophagus, so Barrett's oesophagus sufferers are more prone to GERD pain than normal, at least in the early stages while their is still inflammation. There are other pages in the search that show the same results. I find no information on sensitivity after the inflammation has abated.
  1. Capsaicin receptor (TRPV1) and non-erosive reflux disease explains that there are more nerve fibres in an inflamed oesophagus, so presumably in Barrett's patients.
  2. Increased capsaicin receptor TRPV1 nerve fibres in the inflamed human oesophagus also finds evidence if increased sensitivity when the oesophagus is exposed to acid reflux.
  3. Wikipedia has an article on TRPV1 which clarifies the above reports.

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Barrett's oesophagus, prevalence in the population

  1. This paper finds that Barrett's is far more common than is generally realised. It concludes "The large number of patients, who need to undergo endoscopic surveillance to detect one cancer, raises questions about the value of surveillance endoscopy in patients with short segment or ultra-short segment of Barrett's oesophagus."

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Barrett's oesophagus, symptoms of Barrett's oesophagus is said to have no symptoms. If you search for Barrett's symptoms all you will find are papers talking about the symptoms of reflux and how it causes Barretts.

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Barrett's oesophagus in animals

Barrett's oesophagus occurs in animals other than humans. In fact many laboratory studies of how Barrett's develops have been done in rats, rabbits and dogs.
  1. Experimental columnar metaplasia in the canine oesophagus
  2. Reflux Esophagitis in Three Cats Associated With Metaplastic Columnar Esophageal Epithelium
  3. Validation of a rodent model of Barrett's esophagus using quantitative gene expression profiling
  4. Adenomatous Polyp With Intestinal Metaplasia of the Esophagus (Barrett Esophagus) in a Dog
  5. Bile acid reflux precedes mucosal barrier disruption in the rabbit esophagus.
Columnar epithelial oesophageal cells (as develop in Barret's oesophagus) are apparently normal in fish, reptiles and birds, to judge by the few studies that can be found. So Barrett's appears to be an atavism to a reptilian / piscine (and probably avian) cell structure. As such it seems to be an atavism to a pre-mammalian structure. If so, it is probably possible in nearly all mammals! The following papers discuss the piscine, reptilian or avian oesophagus:5
  1. Histological and Histochemical Studies on the Esophagus, Stomach and Small Intestines of Varanus niloticus - the Nile Monitor - which has columnar cells (similar to Barrett's) lining the oesopishagus.
  2. The anatomy of the oesophagus, stomach and intestine in common wolf fish (Anarhichas lupus L.)
  3. Anatomical observation of the digestive tract in Phascolosoma pacificum Keferstein which is a type of worm found in th Red Sea.
  4. Histological Observation of the Digestive Tract of the Tortoise, Trachemys scripta
animals are also used in experiments to study OAC and barretts, See Bile - is in necessary for Barrett's to form?

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Bile - is in necessary for Barrett's to form?

  1. Chemoprevention of esophageal adenocarcinoma by COX-2 inhibitors in an animal model of Barrett's esophagus
  2. Role of acid and duodenogastric reflux in esophageal mucosal injury: A review of animal and human studies this is only an abstract of a review (so not original data). It states that acid and pepsin are involved in the development of esophageal mucosal injury. It also states that bile without acid may be a contributory factor.
To prove bile is necessary for Barrett's to form you would need to prove that Barrett's cannot form without bile. Negatives in science are notoriously difficult to prove. But what the literature surely demonstrates is that bile-tainted gastric juice is much more dangerous than untainted juice. So there's no real argument! See my own experiments with PPI dosage.

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Bile or duodenogastric reflux

  1. Management of Bile Reflux a paper of questions and answers from Gastroenterology and Hepatology (N Y) 2013 Mar; 9(3): 179-180 states "Bile reflux is very infrequent in healthy individuals." and "It is not possible to distinguish bile reflux from acidic reflux in terms of signs and symptoms."
    My own experience is that differentiation is indeed difficult - but not always impossible. See my notes on bile.
  2. Bile reflux - causes from the Mayo clinic says that bile should not normally enter the stomach, but gives some causes.

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Bile, presence of in the normal gastric fluid

Bile is suspected to be a cause of Barrett's oesophagus. But should bile ever be present in a normal healthy stomach? A search for gastric bile measurement reveals much confusion: most measurements that have been made are on patients with Barrett's oesophagus or other digestive problems. Papers do not say whether PPIs have been taken but it is a safe bet that all of these will have been on PPIs for a significant time. To establish whether PPIs are the cause of such bile, these papers are irrelevant for obvious reasons.
  1. Bile acid concentrations in the refluxate of patients with reflux oesophagitis starts: "Although reflux of bile acids has been implicated in the pathogenesis of reflux oesophagitis, attempts to document this in vivo have failed to detect more than trace amounts of bile acid in the oesophagus..

    Maybe they should measure gastric fluid? The paper then goes on to measure 45 patients with abnormal acid gastro-oesophageal reflux with oesophagitis and 10 controls.

    2 of 10 controls had bile, maximum 40 µmol/l whereas 39 of the 45 patients with reflux had bile (average 50 µmol/l), and 11 very high bile, above 200 µmol/l.

    The paper does not say who was on PPIs - but it is almost certain that the reflux patients were indeed so medicated!

    1. The implications of bile in the stomach a paper from 1969 (so before PPIs) is interesting reading, though it is not definitive. Apparently bile in the stomach is more common in patients with low acidity, which might imply that acid is the mechanism that stops the gall bladder releasing acid. The paper concludes Oesophagitis caused by bile, and bile salts appear to be the irritant responsible, is a vicious disease, much more likely to inflict haemorrhage and stricture on that fragile organ than peptic assault. Patients with gastric atrophy are, with post-operative gastric patients, at much higher risk from such an inflammation than those with normal acid secretion, and their surgical management should therefore be considered more urgently. Which is evidence of the damage gastric bile can cause.
    2. Experiments and Observations on the Gastric Juice, and the Physiology of Digestion is the original book referred to in the above reference. Page 87 refers to gastric bile: with the exceptions that I have mentioned, it (bile) is never found in the gastric cavity in a state of health; it is only in certain morbid conditions that it is found there.

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Bile Reflux caused by PPIs

A Google search for - omeprazole causes bile reflux is of interest. However see also the section below Gall bladder and PPI usage

There is a page describing the regulation of bile release, from the University of Washington. This gives no clues as to how PPIs might affect bile release.

  1. Omeprazole induces altered bile acid metabolism by K Shindo, M Machida, M Fukumura, K Koide, R Yamazaki
    The study was aimed at jejunal flora and found effects which it ascribed to the altered flora affecting the bile mechanism. It was not looking for bile production changes so its conclusions as to mechanism involved are suspect. The increase in bile acid deconjugation products could well be caused by an increase in bile in the stomach due to omeprazole, rather than by the flora changes!
  2. Effect of omeprazole 20 mg twice daily on duodenogastric and gastro-oesophageal bile reflux in Barrett's oesophagus
    Study was based on a 20mG twice daily study. It concluded Treatment of Barrett's oesophagus with omeprazole 20 mg twice daily results in a notable reduction in the exposure of the oesophagus to both acid and duodenal contents. In addition, delivery of duodenal contents to the upper gastric body is reduced. So yes, PPIs can reduce bile. But they can also increase it. See How and why PPIs cause Barrett's oesophagus which changes to oesophageal adenocarcinoma.
  3. Bile Reflux and a defective lower esophageal sphincter
    Misses the point that for bile to be refluxed it must be present in the stomach in the absence of food - so something is interfering with the bile release mechanism!
  4. GERD patients inadequately controlled with PPIs: New Drugs
    An interview with professor Jean-Paul Galmiche, MD, PhD, Gastroenterology Unit, College of Medicine, University of Nantes, Nantes, France.
    Again - misses the point that nobody seems to have realised - problems with any drug are likely to be minimal if the minimum necessary dose is administered. Nobody seems to have published research on the minimum dosage of PPIs.
  5. Heartburn Treatment May Increase Bile Reflux an article from Science Daily.
  6. Omeprazole Side Effects on the Liver. Page says that PPIs disturb bile production!
  7. United States National Library of Medicine page entitled "Effects of rabeprazole, a gastric proton pump inhibitor, on biliary and hepatic lysosomal enzymes in rats." Rats may not be humans, but many humans on PPI feel like lab rats!
  8. Effect of omeprazole 20 mg twice daily on duodenogastric and gastro-oesophageal bile reflux in Barrett's oesophagusby REK Marshall, A Anggiansah, DK Manifold. They found that Omeprazole reduces bile: again, only an abstract, but Omeprezole can alter bile flow by mechanisms unknown.
  9. Determination and pharmacokinetic profile of omeprazole in rat blood, brain and bile by microdialysis and high-performance liquid chromatography by F. C. Chenga, Y. F. Hob, L. C. Hungc, C. F. Chenc and T. H. Tsai
    They found that omeprazole can penetrate the blood-brain barrier. Could be cause of some of its side effects

So there seems to be few references to Omeprazole promoting bile reflux - but at more than one paper realises that it probably does. My own experience is that it certainly does!

  1. The Medscape article Mechanisms of Disease: Carcinogenesis in Barrett's Esophagus: Gastric Acid and Bile Reflux
    Another learned article that warns about problems in treated patients but doesn't suspect that the treatment (PPIs) can actually cause the problem (bile)!
  2. Toxic bile acids in gastro-oesophageal reflux disease: influence of gastric acidity
    Another learned article (a pdf) explaining how bile was measured and proving there are problems with bile reflux - but it does not mention PPIs or omeprazole, so it concluded that the bile is a symptom of Barrett's oesophagus and never considers that it could be a symptom of the treatment!
  3. Are YOUR pills dangerous? Over-prescribing is so rife that millions of us are given drugs we don't even need, worse, they put you at risk of stroke, kidney failure and deadly infection.

    The Mail article uses as one example the over-prescribing of PPIs. Not quite the same as overdosing on PPIs, but the principle is the same!

  4. The role of acid, weak/nonacid, and bile in the genesis of esophageal mucosal damage and reflux symptoms says "The role is changed among patients on proton pump inhibitors with persistent symptoms, where the majority of symptoms are now due to weak acid or bile reflux." However - it does not realise that it is the PPIs that cause the bile reflux!
  5. Effect of the GABAB agonist baclofen in patients with symptoms and duodeno-gastro-oesophageal reflux refractory to proton pump inhibitors is not a study that says PPIs cause bile - but it does state that bile reflux is common in patients that still suffer symptoms while on PPIs. They also have failed to realise that the PPIs may be causing the bile reflux.
  6. Persistent Acid and Bile Reflux in Asymptomatic Patients With Barrett Esophagus Receiving Proton Pump Inhibitor Therapy is another page that finds bile reflux is common in patients on PPIs.
So, if you are on PPIs you may be replacing acid reflux with bile - or with bile-tainted acid! How can you tell the difference?

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Bile Reflux, effects of PPIs on

The astute reader will have noticed my own belief that Barrett's oesophagus is a protection against acid reflux and is not protective against bile. So to be fair, I quote some papers that disagree. I Googled for Proton pump inhibitor bile
  1. Increased acid and bile reflux in Barrett's esophagus compared to reflux esophagitis, and effect of proton pump inhibitor therapy. found that bile reflux is likely to be a causative agent in the formation of Barrett's oesophagus. It also found that such bile reflux was decreased by PPIs. In two patients, however, bile reflux was increased by PPIs.
  2. Prevalence of bile reflux in gastroesophageal reflux disease patients not responsive to proton pump inhibitors. I quote the conclusion: "CONCLUSION: The high percentage of patients poorly responsive to PPI therapy may result from poor control of duodenogastroesophageal reflux. Many patients without esophagitis have simultaneous acid and bile reflux, which increases with increasing esophagitis grade."

    However - the study was based on persons who had been prescribed PPIs and who had responded poorly. It would seem to corroborate the theory that at least some of us develop tolerance to PPIs and that PPIs cause bile reflux in some people.

  3. A Google search for oesophageal cough acid bile reveals several studies which agree that bile reflux is a problem in persistent GERD, but none of them seem to have been done in the absence of medication. PPIs are so commonly used that these patients were almost certainly being medicated and still had bile reflux. This is not inconsistent with my own experience that PPIs actually can cause bile reflux.
  4. Bile Acid at Low pH Reduces Squamous Differentiation and Activates EGFR Signalling in Esophageal Squamous Cells in 3-D Culture. This seems to be the first study that indicates that bile and acid is required for Barrett's oesophagus and its progression.

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Bile, effects on the oesophageal lining

Whatever the truth about PPIs causing bile reflux, there is growing evidence that bile is more damaging to the oesophageal (and, presumably the stomach) lining. PPIs cause definite malfunction of the gall bladder in the majority of cases and as this is likely to cause bile release at the wrong time it is likely that PPIs can cause bile reflux: certainly they did so in myself.

Until the medical profession understand this - and bile as a contributory cause of Barrett's is a clouded view - over use of PPIs will continue! I have no doubt that bile is a contributory cause of progression to cancerous oesophageal adenocarcinoma will also increase.

  1. Columnar Mucosa and Intestinal Metaplasia of the Esophagus is a long article from the annals of Surgery, dated 2000. This admits the picture is cloudy but, well down the article, has a section on Bile salts. It also discusses how the definition of Barrett's oesophagus is not exactly fixed, and its prevalence is not known! One estimate is that, for every known case, there may be 20 or more undiagnosed!
  2. Reflux of duodenal or gastro-duodenal contents induces esophageal carcinoma in rats. Rats are not humans and no study on rats can be taken as proof. However rats are one of the animals in which Barrett's oesophagus can be formed. So this is strong evidence that acid alone may not trigger cancer - but bile does cause progression to cancer.

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Bile - cause of cancer?

If it is correct that bile reflux can cause Barrett's and progression to cancer, then there should be medical papers confirming that Cholecystectomy (removal of the gall bladder) is related to increased cancer risk.
  1. Cholecystectomy and Carcinoma of the Colon does indeed find that Cholecystectomy may be a predisposing factor in the development of cancer of the colon in women. Curiously not so in men!
  2. Association between Cholecystectomy and adenocarcinoma of the esophagus "Conclusions: Cholecystectomy is associated with a moderately increased risk of adenocarcinoma of the esophagus, possibly by the toxic effect of refluxed duodenal juice on the esophageal mucosa. Further studies are needed regarding the link between bile reflux and esophageal carcinogenesis."
  3. Intestinal cancer after cholecystectomy: Is bile involved in carcinogenesis? "Conclusions: Cholecystectomy increases the risk of intestinal cancer, a risk that declines with increasing distance from the common bile duct. Changes in the intestinal exposure to bile might be the underlying biological mechanism."
  4. Cholecystectomy as a risk factor for oesophageal adenocarcinoma "Conclusion: Cholecystectomy appears to be linked to an increased risk of oesophageal adenocarcinoma, but the absolute risk is small."

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Biliary dyskinesia

Gall bladder function is normally measured in terms of Gall Bladder Ejection fraction (GBEF). This is the percentage of bile released when the gall-bladder contracts. It is usually measure by injecting the hormone - CholestoCystoKinin or CCK - that causes it to release bile.

Diskynesia means poor ability to move: in this case it is poor functioning of the gallbladder. Searches for PPI biliary dyskinesia and GallBladder Ejection fraction are revealing:

  1. Acid rebound from NEXIUM!!! Or so I thought. is a forum posting - but her experiences are quite close to and consistent with my own.
  2. Proton Pump Inhibitor May Reduce Gallbladder Function this is a report of a study presented at the 2005 annual meeting of the Society of American Gastrointestinal and Endoscopic Surgeons in Fort Lauderdale, Florida. It is effectively a precis of two papers which establish that there is a high probability that Proton pump inhibitors reduce gallbladder function in most people. However, from my own experience, the problems occur when the PPI dose starts to wear off (particularly when they are taken long term) and the gallbladder starts to recover, releasing bile at the wrong time, when it enters the stomach.
  3. Measurement of Gallbladder Ejection Fraction explains one method of measurement and explains something of how the body controls this. The footnotes explain that the alternative (and probably most common) method is by injection of Kinevac - an artificial form of the hormone CCK (CholestoCystoKinin) which is the body's normal method.

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Cancer risk?

Barrett's oesophagus is said to be a cancer risk, sometimes leading to oesophageal cancer. However cats and dogs get Barrett's and it has been experimentally induced in rats and rabbits (both of which are used to study the phenomenon!) - with great ease. So it is an evolved response to acid reflux and is probably possible in all mammals. This hardly satisfies me that Barrett's is any real cancer risk!

The actual figure of incidence of cancer developing in Barrett's oesophagus is open to doubt: figures once were quoted as high as 5% of Barrett's sufferers develop cancer per year, but other, more recent, studies have shown the risk to be far smaller than that. 0.5% to 0.9% or even as low as 0.22% per year! (See reference 4 below) In other words, the experts simply do not know!

It seems likely that whatever causes oesophageal adenocarcinoma also causes Barrett's oesophagus, on its way to full-blown cancer. So Barrett's is a danger sign and the cause of it should be reduced. However - Barrett's seems not necessarily to be the actual cause but more of a symptom.

Cancer risk generally is also linked variously to certain foods: some foods reduce the risk of cancer, others seem to increase it. Whether this affects orsophageal adenocarcinoma, I would not like to guess. See my own thoughts on Cancer.

  1. Incidence of Progression of Persistent Non-Dysplastic Barrett's Esophagus to Malignancy - a study based on 12,728 patients with NDBE (Non-Dysplastic Barrett's Esophagus) during 2003 and 2013. It found the risk so low that it questioned whether surveillance was worthwhile! "In patients with 2 consecutive endoscopies showing NDBE, the rate of progression to HGD or EAC decreased to 0.55 (95% CI, 0.46-0.64) per 100 person-years (IRR 0.72; 95% CI, 0.60-0.87)." One can assume these patients were all on PPIs. So putting this together with the study that found cancer incidence was 3.9 times higher amongst persons taking PPIs, the risk if you can control symptoms by lifestyle changes is incredibly small!
  2. A paper entitled Pitt Study: Esophageal Cancer Risk Higher in Medically Treated GERD Patients with Fewest Symptoms says "Patients who were adequately managing their GERD symptoms with proton pump inhibitors (PPIs) were 61 percent more likely to have Barrett's esophagus or adenocarcinoma if they reported no severe GERD symptoms, compared to patients taking PPIs who reported severe symptoms." This is a finding which I cannot explain! However if it is another evidence than PPIs should not be used where there are no severe symptoms to treat.
  3. GERD not helpful in esophageal cancer screening. Statistics are confusing: Successful management of symptoms with PPIs apparently increases the chances of cancer developing! The paper says nothing about the chances if you successfully manage symptoms without taking PPIs!
  4. The Medscape article Risk for Progression to Cancer in Barrett's Esophagus. This is a study based on some 8,522 Barrett's 'sufferers' in Northern Ireland over a 7 year period. It found that only 0.22% of Barrett's cases progressed to HGD or cancer per year. That is one person in every 450 per year! Hardly any risk at all!
  5. The Medscape article Risk Factors in the Development of Esophageal Adenocarcinoma reviews various factors which can increase/decrease risk of adenocarcinoma.
  6. Some Observations on the Epidemiology of Barrett's Oesophagus and Adenocarcinoma of the Oesophagus is a long document. It assesses risk at about 0.5% per year.
  7. Bile, not Acid, is Bad Guy in Triggering Precancerous Condition Associated with Reflux Disease so causing bile upset is the last thing that should be done! Put that together with the report on PPIs causing gall-bladder dysfunction ... I leave the obvious conclusion as an exercise for the reader!
  8. Precancerous Condition Associated With Reflux Disease Triggered By Bile - Not Acid this backs up the previous article. Add these to the fact that PPIs cause gallbladder malfunction in most people and that erratic gallbladder function could well lead to bile in the stomach.
  9. ... rat oesophageal squamous cell dysplasia and Barrett's metaplasia induced by duodenal contents reflux says "It is known that bile acids can induce mucosal injury, stimulate cell proliferation, and promote tumorigenesis." Rats aren't humans - but rats are used a lot to test theories. It is also known that PPIs induce bile reflux in a too-high proportion of users - see Gall bladder and PPI usage
  10. The Medscape article Antireflux Surgery and the Risk of Esophageal Adenocarcinoma. I quote a passage: "The authors noted an almost 3-fold increase in cancer risk in people who used medications for reflux.".
  11. Management of Barrett's oesophagus and intramucosal oesophageal cancer: a review of recent development is a U S National library on Medicine article dated September 2012 which generally finds that the risk of progression Barrett's -> adenocarcinoma had been grossly overestimated. It makes interesting reading.
  12. Long Term Proton Pump Inhibitor Use and Gastro-intestinal Cancer is interesting and relatively readable. It describes changes that take place in the gastric lining with long term PPI use and how this could in theory become cancerous. But there is no evidence that it does. It does not mention bile.

I found that PPIs caused, in myself, bile reflux - something I never experienced before taking medication. As PPIs are known (but not generally admitted) to cause gall-bladder malfunction in a large number of people, bile reflux seems likely to be a common effect of taking PPIs. It seems likely that this increase in cancer risk is likely to be due to the bile reflux. See PPIs - long term use increases risk of cancers.

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Digestive and Endocrine systems

There is an interesting series of biomedical hyperbooks at Colorado State University. If you are suffering from digestive problems, you should learn about yourself and how things work. This is a very good place to learn. Some that are of particular relevance are:
  1. Digestive system
  2. Endocrine system
  3. Secretion of Bile and the Role of Bile Acids In Digestion explains the operation of the liver, gallbladder and the hormones that control this.

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Enzyme inhibitors: the way they work

  1. Models of enzyme inhibition
    This is part of a university course on Biochemistry by Dr. Jakubowski. It explains why such inhibitors are almost a switch: either the action is inhibited, it it is not. Increased dosage of PPIs won't result in lower acidity once the level is high enough. A higher dose will simply last longer and may quite likely cause more side-effects. The page is quite technical!
See also how Proton-Pump Inhibitors work.

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Gall bladder and PPI usage

A couple of correspondents emailed me with huge problems with bile reflux and gastritis. Both have had their gall-bladders removed. Both have been on long-term PPIs. So is there a link?

A Google Scholar search for Gall bladder PPI turns up:

  1. Two papers which together illustrate well the scientific method. They noticed an effect - that the gall bladders of many patients worked better after a fundoplication.. They proposed a theory - that this was due to coming off PPIs. They tested the theory. They found that PPIs do indeed, even when used short-term, adversely effect the operation of the gall bladder.
    1. Gallbladder function before and after fundoplication from which a quote: "Unexpectedly, 58% of patients with GERD demonstrated gallbladder motor dysfunction prior to fundoplication, with improvement to normal occurring in most of those studied postoperatively.
      This paper was published in the Journal of Gastrointestinal Surgery, 2002, Volume 6, Issue 6, pp 806-811. The following link is to the paper reporting the test of this theory.
    2. Proton pump inhibitors reduce gallbladder function is a follow-up to the above paper. The authors realised the effects might be due to PPIs so tested 19 volunteers before and after a course of PPIs. 15 of the volunteers had reduced gallbladder function after taking PPIs. In other words PPIs cause Biliary dyskinesia in most of the people tested. The test was done with 40mg/day. Dosage may be key to this matter of gall bladder dysfunction causing bile reflux.

      This report was first published in "Surgical Endoscopy And Other Interventional Techniques." in September 2006, Volume 20, Issue 9, pp 1364-136. Authors are M. A. Cahan, L. Balduf, K. Colton, B. Palacioz, W. McCartney, T. M. Farrell.

      Although 19 is too small a sample to be good statistical proof it is most certainly indicative - but it appears to be the only such research on the subject. Surely there is a link between PPIs and bile reflux and at the very least caring doctors should have heard alarm bells and investigated! Am I glad I took my own health into my own hands and did not listen to the doctors - mainly because they would not listen to me!

  2. The Medscape article Proton Pump Inhibitor May Reduce Gallbladder Function adds a bit more to the above report and explains why some people on PPIs feel nauseous.
  3. The Medscape article Genetic Determinants of Drug-induced Cholestasis and Intrahepatic Cholestasis of Pregnancy mentions PPIs as one of the drugs that can cause cholestasis.
  4. Omeprazole side effects on the liver Not a Scientific paper, but one side effect mentioned is biliary dyskinesia - bile draining slowly from the gall-bladder.

If PPIs cause biliary dyskinesia, the pair of papers above, which were done by a CholestoCystoKinin-stimulated hepatobiliary acid scan, indicate that there are two possibilities: either PPIs interfere with the CCK hormone receptor of the gallbladder, or else PPIs interfere with the motor ability of the gallbladder. But is seems that some 20% of the population tested may be immune to the effect. Why? For more evidence of bile problems see the links above on:

  1. Bile Reflux caused by Omeprazole
  2. Cancer risk?
  3. Bile reflux
  4. Is Barrett's Oesophagus really a pre-cancerous condition?

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Gastric acid - variation with age

It has often been said that gastric acid secretion falls off with age. But this appears not to be true.

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Gastric fluid analysis

An article in Pharmacy times says investigators from Duke University Medical Center and Toronto General Research Institute wondered how PPIs affect gastric fluid - an area few researchers have examined in the past. The article they refer to is below. The analysis looked for bile, gastricsin, trypsin, and pepsin concentrations. Bile and trypsin are not produced in the stomach, but in the liver and pancreas respectively, so should not normally enter the stomach unless the sphincters of Oddi and the pyloric sphincter are incompetent in some way. Gastricsin and pepsin are both produced in the stomach so their percentage may be expected to rise if acid production is reduced.
  1. An assessment of human gastric fluid composition as a function of PPI usage in 40 patients not taking PPIs and 25 on PPIs. It found that
    1. Trypsin was elevated more than 7-fold in patients on PPIs.
    2. Pepsin was reduced almost 30 fold in patients on PPIs.
    3. Bile was elevated 11 fold in patients on PPIs
    4. Of particular interest were substantial differences in the concentrations of digestive enzymes between the two pools). Most (14 of 16) of the pancreatic or hepatic enzymes identified were elevated in patients on PPIs

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Gastric pH in animals

  1. Acidification in monogastric fish states In monogastric animals, including a wide variety of different fish species (ranging from salmon and trout, tilapia, sea bass to pangasius), the chemical breakdown is next to others achieved in the stomach through acidification. Monogastric animals means animals with only one stomach - so would exclude, for instance, ruminants (cows and other bovines).
  2. An article from Nature states The stomachs of most vertebrates operate at an acidic pH of 2 generated by the gastric H+/K+-ATPase located in parietal cells ... Given that insect larval guts were also reported to be alkaline, our discovery raises the hypothesis that the bilaterian ancestor utilized alkaline digestive system while the vertebrate lineage has evolved a strategy to strongly acidify their stomachs.
  3. Digestive system of the cow states The abomasum is also known as the "true stomach."It functions much like the human stomach producing acid and some enzymes to start protein digestion. So even ruminants have acid stomachs!

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Gastro oesophageal reflux disease, general

  1. A general educational site
  2. Importance of Bile Reflux in Barrett's Esophagus
    Joel E. Richter, Department of Gastroenterology, Cleveland Clinic Foundation, Cleveland, Ohio, USA
    An abstract only.

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  1. The Medscape article Gaviscon vs. Omeprazole in Symptomatic Treatment of Moderate Gastroesophageal Reflux found that Gaviscon is as effective as PPIs in moderate cases.

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History of PPIs, Barrett's Oesophagus and oesophagal adenocarcinoma and the rise in incidence

  1. Proton Pump Inhibitors: The Culprit for Barrett's Esophagus? states that The alarming increase of EAC by 600% for the past 25 years suggests that BE has increased as well, as the latter represents the main risk factor for EAC. The author hypothesises that PPIs Transiently Increase Intra-Gastric pH Leading to Bile Salt Toxicity but the real problem is bile. The report is dated 2014, so 25 years ago would have been 1989. Omeprazole was released in 1988 (see next reference)!
  2. A proton-pump inhibitor expedition: the case histories of omeprazole and esomeprazole states that "Omprazole - the first proton-pump inhibitor used in clinical practice - was launched in 1988 as Losec in Europe, and in 1990 as Prilosec in the United States."
  3. Guidelines for the diagnosis and management of Barrett's columnar-lined oesophagus from the British Society of Gastroenterology dated August 2005 states that Barrett's oesophagus, or columnar-lined oesophagus (CLO) as it is more appropriately known, owes its importance to being a precursor lesion of oesophageal adenocarcinoma, the incidence of which has increased three-fold in the last decade and tenfold in the last three decades and currently has the most rapidly increasing incidence of any solid tumour in the western world. The last 3 decades would take us back to 1975. The increase coincides too well with the use of PPIs!
  4. Guidelines on the Diagnosis and Management of Barrett's Oesophagus This page has two links to an update of the link above, first is a re-write dated 2013, second is an update 2015. The first paper states Since the original eponymous description in 1950, there have been numerous definitions of the condition ... Between 1950 and 1970, it was established that Barrett's oesophagus is an acquired condition occurring in response to gastro-oesophageal reflux leading to a columnar lined distal oesophagus.
  5. Wikipedia on Discovery and development of proton pump inhibitors states that omeprazole, was discovered in 1979 ... In 1980, an Investigational New Drug (IND) application was filed and omeprazole was taken into Phase III human trials in 1982 .... and was launched in 1988
  6. Wikipedia on Barrett's oesophagus
  7. Chronic Peptic Ulcer of the oesophagus and oesophagitis. This is first page of the original paper in which Norman Barrett first described the condition. Before that it was simply "oesophagitis". The paper is historically interesting as it goes into the history, with reports back to 1722. Barrett's oesphagus etc. was nothing new!
  8. Ulcers in CLE describes the examination of 44,203 patients between 1966 and 1990 - a period before PPIs were ubiquitous (omeprazole was released in 1988). Carcinoma is not mentioned. GORD clearly is nothing new - what has changed seems to be the prevalence of progression to adenocarcinoma!
  9. Barrett's Esophagus: Emerging Evidence for Improved Clinical Practice The probable presence on columnar metaplasia in the esophagus was reported nearly two centuries ago. The presence of gastric mucosal islands in the esophagus was first described by Schmidt from Halle University in Germany in 1805 (about 150 years before Barrett). So Barrett's oesophagus is nothing new.

    Page of this book says ... published the first article revealing the relationship between the presence of columnar epithelium in the esophagus and EAC in 1952. They proposed that IM (intestinal metaplasia - or Barrett's oesophagus) with goblet cells to be a predisposing cause for EAC in this article.

  10. Dating the rise of esophageal adenocarcinoma: analysis of Connecticut Tumor Registry data, 1940-2007 gives some evidence that the rate of OAC started to rise in the 1950s and plateaued in the 1990s.

    I would not claim that PPIs are the only factor involved in OAC, but this study is sometimes used to prove that PPIs are not to blame. See PPIs - long term use increases risk of cancers for papers that acknowledge this.

I find the far too close correspondence between the rise in OAC or EAC (Oesophageal AdenoCarcinoma) and the increasing use of PPIs just too exact a match to be anything other that hugely suspicious. Until I find a paper proving they both have a common cause, I see no alternative other than that there is direct cause and effect operating. That cause is surely via the effect PPIs have on the gall bladder and consequent bile reflux.

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Increased infection risk

  1. Increased risk of C difficile infections and of fractures
    Two more good reasons to review PPI prescribing.

A search for PPI infection will reveal many more references - infection by clostridium dificile is a well admitted side effect of PPI use.

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Kidney disease caused by PPIs

Proton pumps exist in every cell, but they are commonly not quite tha same sort of pump as in the stomach - H+-ATPase rather than H+/K+-ATPase. Certainly they exist in the kidney, for one of the kidneys' functions is to excrete acid or alkali to keep the blood pH in a narrow healthy band. So some interference with kidney function should not be a surprise! If in doubt, try searching for - renal proton pump.
  1. In early 2016 I received a Medscape article: Proton Pump Inhibitors May Increase Risk for Kidney Disease
    You have to subscribe to Medscape but it's free. The Medscape article links to:
  2. Proton Pump Inhibitor Use and the Risk of Chronic Kidney Disease which found a fairly definite link between PPI use and CKD.
  3. Proton pump inhibitors and the kidney: critical review also states PPIs can damage the kidneys.
  4. A Wikipedia article on Interstitial nephritis (Kidney disease) lists PPIs as one of the causative drugs.
  5. The association of proton pump inhibitors and chronic kidney disease: cause or confounding? is a Review - only an abstract is available without charge. It summarises "The constellation of evidence from all available studies suggests that PPI use is associated with increased risk of adverse kidney outcomes. Exercising vigilance in the use of PPI is warranted."
  6. Nexium, Prilosec & Other PPI Lawsuits outlines the present state (March 2020) of the over 15000 lawsuits that have been filed in USA claiming kidney damage from PPI use.
  7. An article in Nature, February 2019, titled Analysis of postmarketing safety data for proton-pump inhibitors reveals increased propensity for renal injury, electrolyte abnormalities, and nephrolithiasis finds Kidney stones (nephrolithiasis) to be another side effect.

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Larygopharyngeal Reflux

  1. Larygopharyngeal Reflux
    Something I used to suffer so I am well aware of how much nastier bile reflux is than mere acid: at one time (before I was diagnosed, shouting would cause me to cough violently!
  2. The Medscape article The Dreaded Diagnosis of Laryngopharyngeal Reflux Disease
    Apparently the damage to the larynx etc is caused not by acid but more by pepsin in the presence of acid. I myself have experienced refluxed fluid which did not taste particularly acid, nor did it have the bitterness of bile, but it did burn in my larynx. I had hypothesised that this might be pepsin, but could find no confirmation before this paper.

See the section on Pepsin for more references.

Pepsin's action is destroyed by an alkali environment, so the simplest thing to try for pepsin reflux is ti gargle with sodium bicarbonate (baking soda) solution. About 1/2 level teaspoon in about 50cc of water seemed to work well for me at first, but then the refluxate started to become bile tainted and nothing I tried worked - see my Experiments.

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Liver metabolism of PPIs

PPIs are cleared from the blood by the liver, so the metabolic products end up in the bile. If these products are toxic - this could explain the apparent link between long-term PPI usage and gall-bladder dysfunction. There is little reference to the metabolic end-products on the www, but the following are of interest.
  1. Proton pump inhibitors--PPI differences emerge in hepatic metabolism. This states that "Omeprazole and, more markedly, esomeprazole, differ from the other proton pump inhibitors in that their bio-availability increases over the first week of treatment. This is due to a progressive reduction in their hepatic clearance with repeat dosing."
  2. Omeprazole side effects on the liver One side effect mentioned is terminal liver failure, which has occurred in some cases! Another reported effect is biliary dyskinesia - bile drains slowly from the gall-bladder.
See also Tolerance to PPIs.

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Genes are switched off by a process called Methylation. Methylation of the wrong genes leads to cancer. Barrett's Oesophagus is also a Methylation process.
  1. Aberrant DNA Methylation In Oesophageal Cancer And Barrett's Oesophagus is an interesting PHD thesis by Eric Smith. One finding is that fundoplication reduces aberrant methylation whereas proton pump inhibitors do not. So PPIs do not reduce cancer risk.

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Mineral and vitamin malabsorbtion

Acid is required in the digestion to absorb certain minerals. The usual minerals mentioned are calcium and iron. But Magnesium is chemically very similar to calcium so will also be affected. The other affected nutrient is vitamin B12.
  1. Calcium malabsorbtion due to Omeprazole
    Associated problems found were vitamin B deficiency and increased risk of hip fracture.
    Not relevant to bile reflux, but some interesting thoughts.

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Nissen Fundoplication: problems

One popular solution to the problems of reflux is a 'fundo' - properly a Nissen Fundoplication operation. When this is successful it appears to be excellent. However as in any operation there can be complications:
  1. Secondary Achalasia and Other Esophageal Motility Disorders After Laparoscopic Nissen Fundoplication for Gastroesophagal Reflux Disease found about 7% of patients had problems after the operation.

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Omeprazole dosage studies

  1. Study on 10mG/day omeprazole PRICHARD, P. J., YEOMANS, N. D., SHULKES, A., JONES, D. B., BUCKLE, P. J., SMALLWOOD, R. A. and LOUIS, W. J. (1986)
    The effect of omeprazole on 24 h intragastric pH and fasting plasma gastrin during low dosage (10 mg) in the morning or the evening. Journal of Gastroenterology and Hepatology, 1: 289 - 295.
    Departments of Gastroenterology, Austin Hospital, Melbourne, Australia

    Google for PRICHARD, P. J., YEOMANS, N. D., SHULKES, A., JONES, D. B., BUCKLE, reveals many more pages by these researchers.

  2. A paper on the effect of low-dose omeprazole on gastric acid secretion in duodenal ulcer patients does deal with a very low dosage of 5mG/day. However it does not deal with the effect of several 5mG doses per day! My own experiments with PPI dosage showed be that 5mG is below the level needed to produce significant acid suppression.
  3. Omeprazole and Other Proton Pump Inhibitors: Pharmacology, Efficacy, and Safety, with Special Reference to Use in Children has much background information, including information on differing responses to the drug in different patients.
  4. Review article: dual delayed release formulation of dexlansoprazole MR, a novel approach to overcome the limitations of conventional single release proton pump inhibitor therapy tries to suggest ways of overcoming the problems of PPIs not by little and often dosing but by a dual-action delayed release single dose. It is very clear that the doctors do not consider patients capable of taking medicines three or even four times daily so have not considered that. They may be correct.
  5. See my ownexperiments with Omeprazole dosage and side effects

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Oddi, Sphincter of

The sphincter of Oddi controls the release of bile and hepatic juices into the duodenum. It is in fact 3 sphincters in one: the sphincter papillae, the sphincter pancreaticus, and the sphincter choledochus. When the sphincter choledochus is closed, bile backs up into the gall bladder which stores it and concentrates it.

You can look up sites relevant to Sphincter of Oddi dysfunction for yourself. Most deal with it holding back bile rather than letting it leak...

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Pancreatic cancer

There is a paper that found a correlation between pancreatic cancer and PPI use:
    Use of Proton Pump Inhibitors Correlates with Increased Risk of Pancreatic cancer

    This is of interest in view of the fact that PPIs have an adverse effect om the gall bladder and they cause bile reflux. Pancreatic cancer has a low survival rate.

    This paper also quotes another paper that found no such correlation!

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Physiology of reflux disease

The oesophagus is joined to the diaphragm by a ligament called the phrenoesophageal ligament. A Google search for phrenoesophageal ligament hiatal hernia is informative, though some pages are a bit technical.
  1. Pathophysiology of gastroesophageal reflux disease
    A well written and general study intended as a teaching aid.

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Peer review system for scientific papers

Scientific papers are subject to a "Peer Review" process in which scientists of equal status to the writer review the work for errors, originality and general value. This process is intended to stop bad work, and it does so. However it makes it extremely difficult for any researcher to publish any research whose findings seem to contradict current consensus of opinion.
  1. Scrutinizing science: Peer review is an article that explains how the system works. "Peer review does the same thing for science that the "inspected by #7" sticker does for your t-shirt: provides assurance that someone who knows what they're doing has double-checked it."
  2. Nepotism and sexism in peer-review finds faults in the system: "In the first-ever analysis of peer-review scores for postdoctoral fellowship applications, the system is revealed as being riddled with prejudice. The policy of secrecy in evaluation must be abandoned."
  3. Scholarly peer review article from Wikipedia explains the way current consensus of opinion can suppress new ideas. " The peer review process may suppress dissent against "mainstream" theories[58][59][60] and may be biased against novelty.[61] Reviewers tend to be especially critical of conclusions that contradict their own views,[62][63] and lenient towards those that match them."
    Some of the references in this section are worth studying.

    The article also lists examples of failures "Perhaps the most widely recognized failure of peer review is its inability to ensure the identification of high-quality work. The list of important scientific papers that were rejected by some peer-reviewed journals goes back at least as far as the editor of Philosophical Transaction's 1796 rejection of Edward Jenner's report of the first vaccination against smallpox. "

  4. Peer review: a flawed process at the heart of science and journals an article from the Journal of the Royal Society of Medicine makes interesting reading.
  5. Peer Review failure: Science and Nature journals reject papers because "they have to be wrong" is strong criticism of two of the top journals: " My advice to scientists with ground-breaking results is not to even submit papers to Nature or Science any more."

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Pepsin is little referred to but is a major digestive enzyme. It is requires an acid to neutral environment to function. Pepsin is a major problem if refluxate gets beyond the oesophagus, for instance into the airway. From my own experience bile is by far the worst, then pepsin, then acid. Pepsin, unlike bile and acid, has little taste. So quenching the acid in reflux is only a partial solution.
  1. Gastro-oesophageal reflux disease: from pathology to treatment refers to both bile and pepsin reflux.
  2. Reflux Revisited: Advancing the Role of Pepsin - a very interesting treatise on how damaging pepsin can be, and how it is probably pepsin that causes most of the extra-oesphageal symptoms caused by reflux. Pepsin seems to be almost more of a problem than acid - but there is nothing the doctors can do about pepsin reflux, or for that matter, bile reflux so they seem to ignore both these chemicals.

See also the section on Larygopharyngeal Reflux.

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PPIs - how they work

  1. Parietal Cell is a Wikipedia article explaining the parietal cells where acid is produced.
  2. Discovery and development of proton pump inhibitors is another Wikipedia article of relevance. It is somewhat over-technical!
  3. A Google search for Parietal Cell will reveal much more.
  4. Review article: comparison of the pharmacokinetics, acid suppression and efficacy of proton pump inhibitors - also available as a pdf by C. A. M. Stedman and M. L. Barclay from New Zealand. This is very informative which gives a lot of background information on how the drugs work and how they are metabolised. It also explains the differences between the various PPIs.
  5. Many publications say that the efficiency of any dosage of PPIs is proportional to the area under the curve of blood plasma concentration plotted against time. This is stated in the above reference and a Google search for "Proton pump" area under curve should reveal enough to convince you!
  6. Pharmacology of Proton Pump Inhibitors is a somewhat technical article explaining their chemical method of action.
  7. Pharmacology of Proton Pump Inhibitors explains fairly well... However, PPIs cannot inhibit all gastric acid pumps with oral dosing because not all pumps are active during the 90-minute half-life of the PPI in the blood See NOTE. Because PPIs have a short half-life, only 70% of the pump enzymes are inhibited. It takes about 2 to 3 days to reach steady state inhibition of acid secretion. The pump protein has a half-life of about 54 hours in the rat [29] (and probably in humans). Thus about 20% of pumps are newly synthesized over a 24-hour period, and there may be greater pump synthesis at night than during the day. In addition, bedtime administration of PPIs will not add to inhibition of nocturnal acid breakthrough, because the drug will have disappeared by the time nighttime acid secretion is evident. Assuming that about 70% of pumps are activated by breakfast and that the PPI is given 30 to 60 minutes beforehand, it can be calculated that steady state inhibition on once-a-day dosing is about 66% of maximal acid output. Increasing the dose has virtually no effect once optimal dosage has been reached. Increasing the dose frequency does have some effect; a morning dose and an evening dose before meals results in about 80% inhibition of maximal acid output. and In healthy humans, the half-life of PPIs is about 1 hour (9 hours for tenatoprazole), but the duration of acid inhibition is 48 hours because of irreversible binding to the H+/K+-ATPase. The maximal plasma drug concentration (Cmax) and the degree of acid suppression are poorly correlated, but the area under the plasma concentration-time curve (AUC) correlates well with acid suppression.

    NOTE I would take issue with this statement. There is only one critical dose for which this statement is true. If that dose is doubled, the active time will be 2 half-lives. A quadruple dose will take effect for 3 half-lives and 8 times the critical dose would act for 4 half-lives. See my own page on PPI dosage and timing. Is this a misunderstanding of the authors', or fuzzy-thinking? It raises doubts about some of the other other statements.

  8. Proton pump inhibitor-associated pneumonia: Not a breath of fresh air after all? Despite its title, this is readable explanation of how PPI work. Of interest is Inactivated proton pumps are replaced approximately every 50 h[13,15]. Consequently, PPIs may be administered once daily despite the short elimination half-life.
  9. Proton pump activation in stimulated parietal cells is regulated by gastric acid secretory capacity: a human study is a bit technical but is of interest chiefly because it demonstrates the extremely wide variety in the recovery time after a PPI (in this case pantoprazole) has worn off.

    But again there is a serious error: they state Mean proton pump recovery time in stimulated normal human volunteers was 37.1 ± 21.0 hours with a range of 6.7 to 75 hours. They clearly do not know what an arithmetical mean is - for it is the sum of all the measurements divined by the number of measurements, so is a single number without any ± range!

  10. Review article: similarities and differences among delayed-release proton-pump inhibitor formulations A useful compilation article which gives statistics on timescales of various PPIs.
See also how enzyme inhibitors work.

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PPIs - long term use increases risk of cancers.

PPIs are a wonder drug - for short-time use. However long term PPI use can be slightly dangerous. A drug such as a PPI is an "xenobiotic" which is metabolised by the liver. The liver adapts to such toxins by metabolising them quicker, so the effect of a single dose wears off quicker. I experienced noticeable tolerance to PPIs after about 3 1/2 years. PPIs also (in about 75% of people according to the only study that seems to have been made) cause gall bladder malfunction. As a dose wears off the first thing that seems to happen (from my own experience) is that the gall bladder partially recovers and causes bile in the stomach: an unnatural condition. Bile in the stomach probably causes problems there (such as gastritis and even cancer) and will cause bile in any reflux. Bile reflux (from personal experience) is far, far more unpleasant than is plain acid reflux.

This gastric bile seems to occur just before the recovering proton-pumps start to produce acid so shortly after this the refluxed liquid will be bile-tainted acid. Unless you regurgitate gastric juice so you can taste it, the symptoms of acid, bile and acid plus bile are indistinguishable.
A search for PPI cancer or PPI oesophageal cancer is revealing. But there are many published papers which indicate that PPIs do indeed increase the chances on both gastric and oesophageal cancer developing. However none of these identify the mechanism (which I explain on the page: How and why PPIs can cause Barrett's oesophagus which changes to oesophageal adenocarcinoma) so they have almost all been discounted by the medical profession, or even "disproved". However I have found no satisfactory disproof - it is exceedingly difficult to disprove a scientific finding.

  1. Proton pump inhibitors and risk of gastric cancer: a population-based cohort study.. I quote "...the finding of increased incidence (of gastric cancer) among PPI users with most prescriptions and longest follow-up warrants further investigation."
  2. The Medscape article What You Need to Know When You Prescribe a Proton Pump Inhibitor I quote: "Use of PPIs is associated with an increased incidence of gastric cancer."
  3. The Medscape article Antireflux Surgery and the Risk of Esophageal Adenocarcinoma. I quote a passage: "The authors noted an almost 3-fold increase in cancer risk in people who used medications for reflux."
  4. Could Proton Pump Inhibitors Cause Cancer?. I quote "In addition to increased risk of osteoporotic fractures, Clostridium difficile, and other infections, proton pump inhibitors (PPIs) may have also contributed to the sharp rise in gastroesophageal malignant diseases seen over the past 2 decades. This is especially true for esophageal adenocarcinoma, which was previously uncommon, and mirrors the increased use of these drugs."
  5. Proton Pump Inhibitors: The Culprit for Barrett's Esophagus? makes a conclusion that "No cancer-protective effects from PPI's were seen. In fact, high-adherence and long-term use of PPI were associated with a significantly increased risk of adenocarcinoma or high-grade dysplasia."
  6. Evidence That Proton-Pump Inhibitor Therapy Induces the Symptoms it Is Used to Treat Wow! The title of the article is scary enough. But a few quotes:
    1. Since their clinical launch 25 years ago, the use of proton-pump inhibitors has increased progressively with approximately 5% of the developed world now receiving such treatment.
    2. Forty-four percent of previously asymptomatic subjects experienced clinically significant heartburn, acid reflux, or dyspepsia after discontinuing a 2-month course of esomeprazole 40 mg/d compared with 15% after placebo.
    3. The marked trophic effects of proton-pump inhibitor-induced hypergastrinemia caused major concerns during early animal safety tests as a proportion of female rats on long-term omeprazole developed carcinoid tumors of their oxyntic mucosa. Oxyntic mucosa simply means the acid-producing part of the stomach lining.
    This paper is academic rather than scientific as it talks about symptoms: the assumption is made that these are acid rebound, but they could just as easily have been bile rebound! No measurements were made.
  7. Proton pump inhibitor use may not prevent high-grade dysplasia and oesophageal adenocarcinoma in Barrett's oesophagus: a nationwide study of 9883 patients This Danish study actually found that No cancer-protective effects from PPI's were seen. In fact, high-adherence and long-term use of PPI were associated with a significantly increased risk of adenocarcinoma or high-grade dysplasia. This could partly be due to confounding by indication or a true negative effect from PPIs. Until the results from future studies hopefully can elucidate the association further, continuous PPI therapy should be directed at symptom control and additional modalities considered as aid or replacement.
  8. Adverse Effects of Proton Pump Inhibitor Drugs: Clues and Conclusions is a long (9 page) document. The last paragraph on this page (p. 6) concludes The scientific basis for expecting long-term PPI use to cause carcinoid tumors is quite strong and merits serious attention. Hypergastrinemia may also stimulate carcinoid development or growth in other sites. At a minimum, it seems reasonable to discontinue PPI therapy in patients with carcinoid tumors.
  9. Pitt Study: Esophageal Cancer Risk Higher in Medically Treated GERD Patients with Fewest Symptoms says "Patients who were adequately managing their GERD symptoms with proton pump inhibitors (PPIs) were 61 percent more likely to have Barrett's esophagus or adenocarcinoma if they reported no severe GERD symptoms, compared to patients taking PPIs who reported severe symptoms." This is a finding which I cannot explain! However if it is another evidence than PPIs should not be used where there are no severe symptoms to treat.
  10. Proton pump inhibitor use may not prevent high-grade dysplasia and oesophageal adenocarcinoma in Barrett's oesophagus: a nationwide study of 9883 patients The conclusion is that No cancer-protective effects from PPIs were seen. In fact, high-adherence and long-term use of PPI were associated with a significantly increased risk of adenocarcinoma or high-grade dysplasia. This could partly be due to confounding by indication or a true negative effect from PPIs. Until the results from future studies hopefully can elucidate the association further, continuous PPI therapy should be directed at symptom control and additional modalities considered as aid or replacement.
  11. Letter: proton pump inhibitors, GERD and oesophageal adenocarcinoma This starts off The finding that increased proton pump inhibitor (PPI) use is associated with a significantly increased risk of oesophageal adenocarcinoma (OAC)[1] could be a causal relationship rather than coincidence.
  12. Proton Pump Inhibitors Do Not Reduce the Risk of Esophageal Adenocarcinoma in Patients with Barrett‘s Esophagus: A Systematic Review and Meta-Analysis. The conclusion No dysplasia- or cancer-protective effects of PPIs usage in patients with BE were identified by our analysis. Therefore, we conclude that clinicians who discuss the potential chemopreventive effects of PPIs with their patients, should be aware that such an effect, if exists, has not been proven with statistical significance. However the paper does not find that PPIs increase the risk - but the study was not looking for that effect!
  13. In 2016 a paper entitled Maintenance proton pump inhibition therapy and risk of oesophageal cancer was published. Its results: "Among all individuals using maintenance PPI therapy, the overall SIR of oesophageal adenocarcinoma was 3.93". SIR is Standardised Incidence Ratio - which is the the ratio of the results obtained divided by the expected results. In other words the chances of progression found in this study of 796,492 adults are nearly four times higher for PPI users than for non users.

    Medcapes comments on this, in a paper entitled Long-term PPI Use and Increased Esophageal CA Risk include "However, this "surprising" observation comes from a single cohort study that lacks the evidence to demonstrate a causal relationship, warn experts approached for comment." The cause is very definitely Bile reflux induced by the effects of PPIs on the gallbladder.

It is quite clear from these that PPIs do cause OAC. The mechanism is quite clear - even if none of the professionals seem to have worked it out yet!.

See also Cancer risk for more papers.
and History of PPIs, Barrett's Oesophagus and oesophagal adenocarcinoma and the rise in incidence.

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PPIs reduce the cancer risk

There are a number of studies that have found that PPIs have an effect in reducing cancer. I do not necessarily dispute this - for it is quite possible. However it is certain that PPIs interfere with the biliary system and ib so doing can cause bile reflux. Bile reflux is dangerous and the danger from bile reflux almost certainly negates and overrides the small anti-cancer effect of the PPIs. A small benefit plus a large risk adds up to an increased risk! I am not in a position to quantify harm or benefit - but there needs to be more research!

Both these studies are in-vitro - in a test tube. Yes - there is almost certainly a small benefit. Weighed against the overpowering damage caused by bile reflux induced by PPIs.

Apologies for such a short list - but I believe (from my own experience) that any small benefit is far outweighed by the dangerous effect of bile reflux!

  1. Medications (NSAIDs, statins, proton pump inhibitors) and the risk of esophageal adenocarcinoma in patients with Barrett's esophagus. The paper concludes: This observational study indicates that in patients with BE using PPI, NSAID/aspirin, or statin therapy might reduce the risk of developing EAC.
  2. The proton pump inhibitor pantoprazole disrupts protein degradation systems and sensitizes cancer cells to death under various stresses
See PPIs - long term use increases risk of cancers.

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Death associated with PPI use

  1. A paper from BMJ entitled Risk of death among users of Proton Pump Inhibitors: a longitudinal observational cohort study of United States veterans. is a little chilling. The overall risk is slight but, based on a study that tracked 6 million people over nearly 6 years, PPI users were 25% more likely to die than h2 blocker users. No notice was taken as to cause of death, so it could simply be that sick people are prescribed PPIs and tend to die! 25% increase on a risk is quite tiny and would be missed in most studies, but this is another indication that PPIs should not be used unnecessarily.

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PPI usage: Long term studies of

  1. Continuous treatment of Barrett's oesophagus patients with proton pump inhibitors up to 13years: observations on regression and cancer incidence A study by B. T. Cooper, W. Chapman, C. S. Neumann, J. C. Gearty which is encouraging. It finds no adverse affects from long term use.
  2. Anti-ulcer Drugs and Gastric Cancer another abstract - rather more disturbing!
  3. Omeprazole, Hypergastrinemia, and Gastric Carcinoid Tumors evidence that PPIs cause hypergastrinemia. It also notices rebound symptoms after discontinuing usage. An extract only : full text is chargeable!

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PPIs - their half life

PPIs have a short half life in the blood plasma as they are quickly eliminated by the liver. Their effectiveness is very much down to the area under the curve plotting blood plasma levels variation with time. However liver elimination is not the only time constant involved - see Half-life: what does it mean?

Various sites give various figures:

  1. Proton Pump Inhibitors: An Update says 1 to 2 hours.
  2. NIH public assess quotes 90 minutes.
  3. Wikipedia says 60-90 minutes.
  4. A focus on parietal cells as a renewing cell population is not about PPIs, but about the cells they are aimed at. parietal cells belong to a continuously renewing epithelial cell lineage. ... The production of a new parietal cell takes about 2 days. However, mature parietal cells have a long lifespan during which they migrate bi-directionally while their functional activity for acid secretion gradually diminishes. Following an average lifespan of about 54 days, in mice, old parietal cells undergo degeneration and elimination.
Incidentally a search for PPI plasma "half life" reveals many attempts to search for PPIs with longer plasma half lives, but nobody seems to realise that the way to deal with a short half-life is to increase the frequency of doses! That also means the doses can be reduced and the total intake also reduced.

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Rebound acidity after discontinuing PPIs

  1. A Norwegian study explain the mechanism The authors of this are Helge L. Waldum, Gunnar Qvigstad, Reidar Fossmark, Per M. Kleveland & Arne K. Sandvik whose names may be rewarding in your searches

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Reflux pains may be reduced by atropine

  1. Atropine inhibits gastric distension and pharyngeal receptor mediated lower oesophageal sphincter relaxation explains that reflux sufferers may get relief via atropine. Reflux is made worse by PPIs.

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Side effects of PPIs

Considering how radically PPIs disturb the human endocrine balance and how different they make the biochemistry, it is remarkable they have so few side effects! But they are not 100% safe. Several side-effects have been noted in medical papers. But here are also, in almost all cases, other papers that fail to find any such correlation but absence of evidence is not evidence of absence! The fact that most of these side effects are so difficult to prove does indicate they are either not common or not severe.

Proton Pump Inhibitor Lawsuits makes interesting reading.

DrugWatch has a page on PPI side effects.

A pdf titled Potential adverse effects of long term use of Proton Pump Inhibitors lists most of the side effects below.

An article in Nature, February 2019, titled Analysis of postmarketing safety data for proton-pump inhibitors reveals increased propensity for renal injury, electrolyte abnormalities, and nephrolithiasis lists many side effects.

  1. Brain - dementia
  2. Chronic cough
  3. Gall bladder
  4. Kidneys
  5. Liver
  6. Mineral and vitamin deficiency
  7. Various
  1. Brain
    1. Determination and pharmacokinetic profile of omeprazole in rat blood, brain and bile by microdialysis and high-performance liquid chromatography by F. C. Chenga, Y. F. Hob, L. C. Hungc, C. F. Chenc and T. H. Tsai
      The abstract of the report concludes: the results indicated that omeprazole was able to penetrate the blood-brain barrier.
      This could be a cause of the reported correlation between PPI use and dementia. Or it could simply be that PPIs are prescribed willy-nilly to old people who are already suffering dementia!
    2. Cognitive impact after short-term exposure to different proton pump inhibitors. This is a paper that found PPIs had statistically and clinically significant impairment in visual memory, attention, executive function, and working and planning function.
    3. Risk of dementia in elderly patients with the use of proton pump inhibitors. A study of 3,327 community-dwelling persons aged 75 years and over found that patients receiving PPI medication had a significantly increased risk of any dementia.
    4. Yet another study on Proton Pump Inhibitor Use and Dementia Risk: Prospective Population-Based Study. found there was no correlation,
    5. Proton Pump Inhibitor Use and Dementia Risk a study of 3,484 individuals aged 65 and older without dementia at study entry. This found that, over 7.5 years Proton pump inhibitor use was not associated with dementia risk, even for people with high cumulative exposure.
  2. Cough
  3. My own experience is that there are indeed cough receptors in the oesophagus and that these are activated by bile and by acid. Bile (or acidic bile) is much more irritating than is plain acid.

    A google search for oesophageal cough is revealing

    1. Gastroesophageal reflux and chronic cough
    2. National Lung Health Education Program's page on Chronic cough
  4. Gut
    1. The Medscape article Proton Pump Inhibitors Linked to C difficile Diarrhea
    2. Significant Association Between the Use of Different Proton Pump Inhibitors and Microscopic Colitis found a strong association between microscopic colitis and ongoing use of proton pump inhibitors, especially lansoprazole. Colitis is inflammation of the colon (large intestine) which results in chronic diarrhoea.
  5. Kidneys
    1. Common Heartburn Drugs Linked to Kidney Failure in the Elderly - not a high risk, the study found about 8 cases in 100 more than the control subjects.
    2. Proton Pump Inhibitors and Risk of Incident CKD and Progression to ESRD We used Department of Veterans Affairs national databases to build a primary cohort of new users of PPI (n=173,321) and new users of histamine h2-receptor antagonists (h2 blockers; n=20,270) and followed these patients over 5 years to ascertain renal outcomes ... the PPI group, compared with the h2 blockers group, had an increased risk of incident eGFR ... and of incident CKD.
      eGFR is short for estimated glomerular filtration rate. Your eGFR is a number based on your blood test for creatinine, a waste product in your blood. It tells how well your kidneys are working.
  6. Liver
    1. Omeprazole Side Effects on the Liver. Page says that PPIs disturb bile production!
    2. More disturbing is PPI and H2 Receptor Antagonist Use and Risk of Liver Cancer which concluded We found some evidence that PPI use was associated with liver cancer. Whether this association is causal or reflects residual confounding or reverse causation requires additional research.
  7. Mineral and vitamin deficiency
    1. Magnesium deficiency - Hypomagnesaemia due to proton-pump inhibitor therapy. This is so serious that the UK government has released a warning about PPIs and Hypomagnesaemia
    2. The Medscape article PPIs and Vitamin B12 Deficiency: Is There a Link? PPI usage is apparently associated with vitamin B12 deficiency:: this can lead to anaemia, nerve damage, dementia, and more.
  8. Various
    1. Proton Pump Inhibitors - A Risky Experiment? lists several side-effects.
    2. Proton Pump Inhibitors Accelerate Cellular Aging - a quote from this paper: Doctors have been giving the PPIs with the understanding that these drugs are specific for the acid pump in the stomach. What we have found is that another acid pump is affected, and this causes 'garbage' (damaged proteins) to aggregate in the cells, (which) causes the cells to age faster, he explained.

      This study provides a plausible unifying mechanism for accumulating reports that PPI users are at increased risk for heart attack, kidney problems, and dementia, continued Dr. Cooke .

    3. Potential adverse effects of proton pump inhibitors

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Trypsin is a digestive enzyme produced in the pancreas and discharged through the sphincter of Oddi into the duodenum. So it should not be present in the stomach - unless the pyloric sphincter is faulty. In which case bile will also be present.
  1. The paper Role of pancreatic trypsin in chronic esophagitis induced by gastroduodenal reflux in rats demonstrates that trypsin reflux is harmful.
  2. Another abstract Active trypsin and reflux oesophagitis: an experimental study in rats. confirms the harmful nature.

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Omeprazole tolerance

  1. Wikipedia article on drug tolerance
  2. Anticonvulsant activity of omeprazole in rats. An abstract of an article detailing a study of Omeprazole in rats. The study was not to do with it's action in suppressing acid. However the rats rapidly developed tolerance.
  3. Tolerance and Resistance to Drugs explains "Usually, tolerance develops because metabolism of the drug speeds up (often because the liver enzymes involved in metabolizing drugs become more active) and because the number of sites (cell receptors) that the drug attaches to or the strength of the bond (affinity) between the receptor and drug decreases"
  4. Comparison of inhibitory effects of the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome p450 activities a very technical paper. Human cytochrome p450 is a group of enzymes that metabolise PPIs. The paper concludes that PPIs in general partially suppress the enzymes that metabolise PPIs. So that should mean that their potency increases, at least initially. With long term use tolerance still seems likely.
So although the theory states that long term use of PPIs should result in their being cleared faster by the liver so that some tolerance develops, this has not been studied. My own experiments with PPIs seemed to indicate that this was indeed happening after a 4 year course.

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Visceral fat, reflux and Barrett's

When first diagnosed with Barrett's I suspected that, although I was not overweight I was too fat for my own good. At that time I had a BMI of 23.8, near the top of the then so-called healthy range - which seems to have been decreased since! I lost weight, my reflux symptoms and general health improved. I suspected that visceral fat was the culprit.
  1. Ratio of visceral abdominal to subcutaneous fat linked to Barrett's esophagus
    The article doesn't mention hiatal hernia, so gives no clue as to whether mechanical effects of visceral fats are to blame or whether there are other explanations. Fats are now known to be generators of several hormones.
  2. The Medscape article The Effects of Obesity on Oesophageal Function, Acid Exposure and the Symptoms of Gastro-Oesophageal Reflux Disease
    a study to investigate the hypothesis that the mechanical effects of obesity are to blame. It found no evidence to this effect - but absence of evidence is not evidence of absence (and they did not directly measure visceral fat), but there may be more to the link than simple visceral fat.
  3. The Medscape article entitled Asthma, PTSD, BMI Linked to GERD in 9/11 Responders found that there was indeed a link between body mass index (BMI) and the likelihood of reflux.
The question I still ask is "Do skinny people suffer from reflux?" I suspect Yes - but far less than other people.

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Weight gain on PPIs

  1. Long-term treatment with proton pump inhibitor is associated with undesired weight gain
    An interesting one: weight gain implies one of the following:
    1. Alteration in diet
    2. Increase in absorption of the existing diet - which could be caused by a change in gut microbiota - something almost certain to happen with PPIs.
    3. Water retention
    The study makes no attempts to guess which. From by own experience, an awareness of food is rather necessary: there are for example certain foods which are not as fattening as their calorie count indicates. Coconut and peanuts are two!

Page contents Index to GORD info

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Page first published July 2015.
Last modified: April 06 2021 08:38:01.
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