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:

Many (most) medical papers are academic! Scientific medical papers are few.

• Alternative therapies for acid reflux
• Barrett’s oesophagus sufferers are more prone to GERD pain than normal
• Barrett’s oesophagus in animals
• Bile or duodenogastric reflux
• Bile Reflux caused by Omerazole
• Bile Reflux, effects of PPIs on
• Bile, effects on the oesophageal lining
• Cancer risk?
• Digestive and Endocrine systems
• Duodenogastric or Bile reflux
• Enzyme inhibitors: the way they work
• Gall bladder and PPI usage
• Gastro oesophageal reflux disease, general
• Gaviscon
• History of PPIs, Barrett’s Oesophagus and oesophageal adenocarcinoma
• Increased infection risk
• Kidney disease caused by PPIs
• Larygopharyngeal Reflux
• Liver metabolism of PPIs
• Mineral malabsorbtion
• Nissen Fundoplication: problems
• Omeprazole dosage and other studies
• Omeprazole tolerance
• Oddi, Sphincter of
• Physiology of reflux disease
• Pepsin
• PPIs – how they work
• PPIs – long term use increases risk of cancers.
• PPI usage: long term studies of
• PPI usage – side effects of
• PPIs – their half life
• Rebound acidity after discontinuing PPIs
• Reflux pains may be reduced by atropine
• Side effects of PPI usage
• Visceral fat, reflux and Barrett’s
• Weight gain on PPIs

Alternative therapies for acid reflux

PPIs are the conventional cure, but there are other possibilities

Hypnosis

• 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!
• 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

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

The Medscape article Can Complementary and Alternative Therapies Relieve GERD Symptoms? says that this is indeed useful.

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.

• 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.
• 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.
• Wikipedia has an article on TRPV1 which clarifies the above reports.

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.

• Chemoprevention of esophageal adenocarcinoma by COX-2 inhibitors in an animal model of Barrett’s esophagus
• 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.
• Experimental columnar metaplasia in the canine oesophagus
• Reflux Esophagitis in Three Cats Associated With Metaplastic Columnar Esophageal Epithelium
• Validation of a rodent model of Barrett’s esophagus using quantitative gene expression profiling
• Adenomatous Polyp With Intestinal Metaplasia of the Esophagus (Barrett Esophagus) in a Dog
• Bile acid refflux precedes mucosal barrier disruption in the rabbit esophagus.

Columnar epithelial oesophageal cells (as develop in Barret’s oesophagus) are apparently normal in reptiles. 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!

• Histological and Histochemical Studies on the Esophagus, Stomach and Small Intestines of Varanus niloticus
• The anatomy of the oesophagus, stomach and intestine in common wolf fish (Anarhichas lupus L.)
• Anatomical observation of the digestive tract in Phascolosoma pacificum Keferstein
• Histological Observation of the Digestive Tract of the Tortoise, Trachemys scripta

Bile or duodenogastric reflux

• 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 difficult – but not always impossible. See my notes on bile.
• Bile reflux – causes from the Mayo clinic says that bile should not enter the stomach, but gives some causes.

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.

• 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!
• 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. However my findings are that a 20mG dose is in fact a massive overdose!
• 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!
• 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 has researched minimum dosage of PPIs, but see the paper on the effect of low-dose omeprazole!
• Heartburn Treatment May Increase Bile Reflux an article from Science Daily.
• Omeprazole Side Effects on the Liver. Page says that PPIs disturb bile production!
• 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!
• 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
• 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!

Maybe a Google search for Barrett’s bile or proton pump bile refkux or will reveal more?

• 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)!
• 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!
• 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!
• 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!
• 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.
• 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.

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 forProton pump inhibitor bile

• 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.
• 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.

• 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 certaily being medicated and still had bile reflux. This is not inconsistent with my own experience that PPIs actually can cause bile reflux.
• 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.

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 reference to bile as a contributory cause of Barrett’s is a clouded view! But I have no doubt that bile is a contributory cause of progression to cancer.

• 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!
• 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.

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 – 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 have been quoted as high as 5% of Barrett’s sufferers develop cancer per year, but other studies have shown the risk to be far smaller than that. 0.5% to 0.9% or even as low as 0.2% per year! In other words, the experts simply do not know!

It seems certain 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 to be the actual cause.

Cancer risk is also linked variously to certain foods: some foods reduce the risk of cancer, others seem to increase it. See my own thoughts on Cancer.

• Esophageal cancer risk overblown, study suggests a CBS news page.
• Esophageal Cancer Risk Higher in Medically Treated GERD Patients With Fewest Symptoms
• 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! Hardly any risk at all!
• The Medscape article Risk Factors in the Development of Esophageal Adenocarcinoma reviews various factors which can increase/decrease risk of adenocarcinoma.
  Incidentally, Medscape is worth subscribing to – you can get email alerts of any papers relevant to your condition.
• 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.
• 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 an an exercise for the reader!
• 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 malfuction in most people and that erratic gallbladder function could well lead to bile in the stomach.
• … 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
• 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.”.
• Management of Barrett‘s oesophagus and intramucosal oesophageal cancer: a review of recent development is a U S National library on Medicine artice dated September 2012 wghich generally finds that the risk of progression Baqrrett’s -> adenocarcinoma had been grossly overestimated. It makes interesting reading.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.

  This passage is from the first part of the report, based on a population study over 1995-1997, when PPI usage was common.

• 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.

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:

• Digestive system
• Endocrine system
• Secretion of Bile and the Role of Bile Acids In Digestion explains the operation of the liver, gallbladder and the hormones that control this.

Enzyme inhibitors: the way they work

• 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. A higher dose will last longer and will likely cause more side-effects.

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:

• Potential adverse effects of proton pump inhibitors
• Omeprazole side effects on the liver One side effect mentioned Cholestasis – bile draining slowly from 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.

• 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.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 statistically useful – but it appears to be the only such research. Surely there is such a link 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!

• 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.
• 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.

For more evidence of bile problems see the links above on:

• Bile Reflux caused by Omerazole
• Cancer risk?

Gastro oesophageal reflux disease, general

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

Gaviscon

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

History of PPIs, Barrett’s Oesophagus and oesophagal adenocarcinoma

• 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 report is dated 2014, so 25 years ago would have been 1989.
• A proton-pump inhibitor expedition: the case histories of omeprazole and esomeprazole states that Omprazole – the first proton-pump inhibitor used inclinical practice – was launched in 1988 as Losec in Europe, and in 1990 as Prilosec in the United States.

Increased infection risk

• 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.

Kidney disease caused by PPIs

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 shuould not be a surprise! If in doubt, try searching for – renal proton pump.

• 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:
• Proton Pump Inhibitor Use and the Risk of Chronic Kidney Disease which found a fairly definite link between PPI use and CKD.
• Proton pump inhibitors and the kidney: critical review also states PPIS can damage the kidneys.
• A Wikipedia article on Interstitial nephritis (Kidney disease) lists PPIs as one of the causative drugs.

Larygopharyngeal Reflux

• 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.

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 seems to work well for me.

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.

• 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.

• 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.

Mineral malabsorbtion

• 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.

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:

• 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.

Omeprazole dosage studies

• 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, AustraliaOne of the lowest dosage studies I have found – yet a 10mG single dose is still an overdose.

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

• 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!
• 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.
• 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.
• Omeprazole dosage and side effects – Why current recommendations are wrong

Omeprazole tolerance

• WebGERD claims tolerance does not alter.
• Wikipedia article on drug tolerance
• An abstract of an article detailing a study in rats. They rapidly developed tolerance.

A google search for oesophageal cough is revealing

• Gastroesophageal reflux and chronic cough
• National Lung Health Education Program’s page on Chronic cough

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.

• Sphincter of Oddi Dysfunction: Introduction – a page from John Hopkins Medicine introducing the subject. It has a good diagram.

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.

• Pathophysiology of gastroesophageal reflux disease
  A well written and general study intended as a teaching aid.

Pepsin

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.

• Gastro-oesophageal reflux disease: from pathology to treatment refers to both bile and pepsin reflux.
• 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.

PPIs – how they work

• Parietal Cell is a Wikipedia article explaining the parietal cells where acid is produced.
• Discovery and development of proton pump inhibitors is another Wikipedia article of relevance.
• A Google search for Parietal Cell will reveal much more.
• 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.
• 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!

PPIs – long term use increases risk of cancers.

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 gallbladder 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.
A search for PPI cancer or PPI oesophageal cancer is revealing:

• 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.”
• 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.”
• 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.”
• 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.”

See also Cancer risk for more papers.

PPI usage: Long term studies of

• Continuous treatment of Barrett’s oesophagus patients with proton pump inhibitors up to 13 years: 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.
• Anti-ulcer Drugs and Gastric Cancer another abstract – rather more disturbing!
• 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!

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:

• Proton Pump Inhibitors: An Update says 1 to 2 hours.
• NIH public assess quotes 90 minutes.
• Wikipedia says 60-90 minutes.

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.

Rebound acidity after discontinuing PPIs

• 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

Reflux pains may be reduced by atropine

• 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.

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.

• Omeprazole Side Effects on the Liver. Page says that PPIs disturb bile production!
• 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
• The Medscape article Proton Pump Inhibitors Linked to C difficile Diarrhea
• The Medscape article Overutilization of Proton-pump Inhibitors states links have been found to Clostridium difficile-associated diarrhoea, community-acquired pneumonia, bone fracture, nutritional deficiencies, and interference with metabolism of antiplatelet agents.
• Proton Pump Inhibitors — A Risky Experiment? lists several side-effects.
• Hypomagnesaemia due to proton-pump inhibitor therapy
• The Medscape article PPIs and Vitamin B12 Deficiency: Is There a Link? PPI usage is apparently associated with vitamin B deficiency:: this can lead to anaemia, nerve damage, dementia, and more.
• 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.
• 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, Dr. Cooke said.

Visceral fat, reflux and Barrett’s

When first diagnosed with Barrett’s I suspected that, although I was not overweight (I had a BMI near the top of the so-called healthy range) I was too fat for my own good. I lost weight, by reflux symptoms and general health improved. I suspected that visceral fat was the culprit.

• 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
• 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 – 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.

Weight gain on PPIs

• Long-term treatment with proton pump inhibitor is associated with undesired weight gain
  An interesting one: weight gain implies one of the following:
  • Alteration in diet
  • Increase on absorption of the existing diet
  • 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!

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