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:
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.
- 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
- 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
- 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
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.
The Medscape article Can Complementary and Alternative Therapies Relieve GERD Symptoms? says that this is indeed useful.
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
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 reflux 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, 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.
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
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.
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
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.
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
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 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!
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.
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.