Barrett's oesophagus, Omeprazole dosage and bile reflux: links
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...
PPIs are the conventional cure, but there are other possibilities
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!
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.
Probably the most important alternative therapy to Proton Pump Inhibitors is to use the old, time proven, traditional antacids. There are so many, it probably deserves a separate page. So watch this site - or use the contact button!
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.
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::
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.
Management of Bile Reflux a paper of questions and answers from Gastroenterology and Hepatology (N Y). 2013 Mar; 9(3): 179180. 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 difficult - but not always impossible. See my notes on bile.
Bile reflux - causes from the Mayo clinic says that bile should not normally enter the stomach, but gives some causes.
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.
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 (aberage 50 µmol/l), and 11 very high bile, above 200 µmol/l.
The paper does not say who wa on PPIs - but it is almost certain that the reflux patients were indeed so medicated!
The implications of bile in the stomach a paper from 1969 (so before PPIs) is interesting reading, though it is not definitive. However it concludes There is meantime a practical application of this knowledge. 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.
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!
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.
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!
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
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.
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.
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.
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!
Gall bladder function is normally measured in terms of GallBladder 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:
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.
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.
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! In other words, the experts simply do not know!
It seems likely that whatever causes oesophageal adenocarcoinoma 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.
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!
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!
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.
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:
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!
Two papers which together illustrate well the scientific method. They noticed an effect - that the gall bladers 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.
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.
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!
If PPIs cause cholestasis, 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:
An article in Pharmacy times says investigators from Duke University Medical Center and Toronto General Research Institute wondered how PPIs affect gastric fluidan 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.
Trypsin was elevated more than 7-fold in patients on PPIs.
Pepsin was reduced almost 30 fold in patients on PPIs.
Bile was elevated 11 fold in patients on PPIs
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
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).
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.
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!
History of PPIs, Barrett's Oesophagus and oesophagal adenocarcinoma and the rise in incidence
Proton Pump Inhibitors: The Culprit for Barretts 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)!
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!
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.
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!
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 prevalance of progression to adenocarcinoma!
Barrett's Esophagus: Emerging Evidence for Improved Clinical PracticeThe 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.
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.
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.
Proton pumps exist in almost every cell. 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.
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!
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.
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 seems to work well for me.
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.
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.
Omeprazole side effects on the liver One side effect mentioned is terminal liver failure, which has occurred in some cases! Another reported effect is Cholestasis - bile drains slowly from the gall-bladder.
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:
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.
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.
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.
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."
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."
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 and may be biased against novelty. Reviewers tend to be especially critical of conclusions that contradict their own views, 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. "
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.
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.
Many publications say that the efficiency of any dosage of PPIs is proportional to the area under the 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!
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  (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 concentrationtime 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.
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!
PPIs are a wonder drug - for short-time use. However long term PPI use can be 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 occurs just before the recovering proton-pumps start to produce acid so shortly 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 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 satifactory disproof - it is exceedingly difficult to disprove a scientific finding.
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."
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.
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.
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.
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.
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?
A focus on parietal cells as a renewing cell population is not about PPIs, but about the cells they aare 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.
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 and such correlation. :absence of evidence is not evidence of absence! But the fact that most of these side effects are so difficult to prove does indicate they are either not common or not severe.
There is a problem with almost all research papers, but particularly. 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 to find what you expect. Indeed, I could be accused of that - but in my case I found that, when experimented, I suffered from Bile reflux. Not being in a position to do useful research I set out to try and explain from published research whether I was unique and what was causing this bile reflux.
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) much more so than acid.
Proton Pump Inhibitors and Risk of Incident CKD and Progression to ESRDWe 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.
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 .
Trypsin is a digestive enzyme produced in the pancreas and discharged thruioghthe 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.
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"
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.
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.
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!