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ACID REFLUX AND PPI's - the implications for levels of Vitamin B12.

gutlesswonder
gutlesswonder
6 Replies

[ Poster's comment. "Despite being the principal learned article on the subject this is an elegant and readily understood summary of the extraordinarily subtle and complex processes involved in the ingestion and acquisition of this vital, life-sustaining substance."]

The Mechanism for Omeprazole Induced Vitamin B12 Deficiency and Risk of Developing Macrocytic Anemia, Hyperhomocysteinemia, and/or Neuropathy

Summary:

The chronic use of proton pump inhibitors such as omeprazole (Prilosec) is fairly common in medical practice especially for gastroesophageal reflux disease (GERD)[GORD] or in patients at increased risk of peptic ulcer disease (PUD), but has been associated with causing vitamin B12 deficiency.

If vitamin B12 is ingested in its free (or non-protein bound) form, it will bind to a carrier protein known as R-binders or transcobalamin I that is secreted by both the salivary glands in the oropharynx and the gastric mucosal cells within the stomach.

If the vitamin B12 is ingested in its protein bound form, it must first undergo a proteolytic cleavage in the stomach or duodenum where it will bind to an R-binder and enter into the duodenum for further cleavage.

Upon entry into the second segment of the duodenum, the pancreas will secrete additional protease which will then degrade the R-binders holding onto the vitamin B12. It is at this point that vitamin B12 will bind to or complex with intrinsic factor for the remainder of its journey to the ileum of the small intestine for absorption.

Omeprazole's ability to suppress gastric acid production can impair the conversion of pepsinogen to pepsin, which can affect the ability of protein bound vitamin B12 to be freed for additional preparations for absorption will be compromised.

Editor-in-Chief: Anthony J. Busti, MD, PharmD, FNLA, FAHA

Reviewers: Donald S. Nuzum, PharmD, BCACP, CDE

Last Reviewed: October 2015

Explanation

The chronic use of proton pump inhibitors, such as omeprazole (Prilosec), is fairly common in medical practice especially for gastroesophageal reflux disease (GERD) or in patients at increased risk of peptic ulcer disease (PUD). The increased utilization of omeprazole is also likely due to its availability over-the-counter (OTC) and use without a prescription or knowledge of the healthcare professionals caring for that patient. While omeprazole is useful for GERD and PUD, its use is not without the increased risk of other complications, such as an increased risk for aspiration pneumonia in certain patients, clinically relevant drug-drug interactions, and complications related to vitamin B12 deficiency, such as macrocytic anemia, hyperhomocysteinemia, and/or neuropathies.1-7

The focus of this article is related to the mechanism by which omeprazole could cause a deficiency in vitamin B12. In order for this interaction to make sense, a brief description of the normal sequence of events for vitamin B12 absorption must be understood. If vitamin B12 is ingested in its free (or non-protein bound form) [that is as a nutritional supplement produced industrially by bacterial fermentation], it will bind to a carrier protein known as R-binders or transcobalamin I that is secreted by both the salivary glands in the oropharynx and the gastric mucosal cells within the stomach.1,2,8 The free vitamin B12 ingested by mouth will remain in the bound form with an R-binder until it reaches the second segment of the duodenum in the small intestine.

If the vitamin B12 is ingested in its protein bound form [that is it originates in animal or vegetable tissues as a foodstuff], then it must first undergo a proteolytic cleavage in the stomach or duodenum where it will bind to an R-binder and then enter into the duodenum for further cleavage.1,2,8 This proteolytic cleavage is mostly dependent on the functional activity of pepsin. As a reminder, the chief cells within the stomach will secrete the pepsinogen into the lumen of the stomach. The presence of the hydrochloric acid, provided by the parietal cells, is necessary to convert the pepsinogen to pepsin. Omeprazole's ability to inhibit acid production by the parietal cell is contributing to a large portion of its effect on protein-bound vitamin B12. The functionally active pepsin can then degrade the newly ingested protein source holding onto to the vitamin B12. Upon this protein degradation, the free vitamin B12 will then proceed as above to be bound to an R-binder or transcobalamin I for entry into the duodenum. Therefore, regardless of the molecular state of vitamin B12 ingested, it is mostly delivered to the duodenum as a complex with an R-binder.

Intrinsic factor is also present in the gastric and intestinal contents that contain the vitamin B12 complexed to R-binders and being delivered to the duodenum. In addition to the hydrochloric acid secreted from the stomach, the properly functioning parietal cells also secrete intrinsic factor, however nothing is bound to the intrinsic factor at this point. Upon entry into the second segment of the duodenum, the pancreas will secrete additional protease, which will then degrade the R-binders holding onto the vitamin B12. It is at this point that the vitamin B12 will bind to (or complex with) intrinsic factor for the remainder of its journey to the ileum of the small intestine for absorption. Assuming a functionally intact ileum, the vitamin B12/intrinsic factor complex is taken up into the enterocyte at this point in the small intestine. The absorbed vitamin B12 then binds to transcobalamin II where approximately 50% of the vitamin B12 will be delivered to the liver and the remainder will be delivered to other tissues.

As indicated earlier, omeprazole's ability to suppress gastric acid production can impair the conversion of pepsinogen to pepsin. If pepsin formation is compromised, the ability of protein bound vitamin B12 to be freed for additional preparations for absorption will be compromised.2-7 In addition, the increase gastric pH also contributes to a greater degree of bacterial colonization and replication within the gastrointestinal tract, thus potentially leading to bacterial overgrowth.2 If bacterial overgrowth also occurs then additional vitamin B12 that was originally ingested for absorption will be utilized by the enteric bacteria thereby reducing the final amount of vitamin B12 available for absorption in the terminal ileum of the small intestine.

Therefore, since omeprazole only impairs the absorption of protein bound vitamin B12 from animal-derived dietary sources, the use of free or unbound vitamin B12 (such as cyanocobalamin) [as a supplement] are not affected and can be safely used to correct the vitamin B12 deficiency especially if the patient cannot stop taking the omeprazole.

References:

Institute of Medicine. Food and Nutrition Board. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: National Academy Press, 1998.

National Institutes of Health. Office of Dietary Supplements. Dietary Supplement Fact Sheet: Vitamin B12. Bethesda, Maryland. 05/26/2010.

Ruscin JM, Page RL 2nd, Valuck RJ. Vitamin B(12) deficiency associated with histamine (2)-receptor antagonists and a proton-pump inhibitor. Ann Pharmacother 2002;36:812-6.

Saltzman JR, Kemp JA, Golner BB et al. Effect of hypochlorhydria due to omeprazole treatment or atrophic gastritis on protein-bound vitamin B12 absorption. J Am Coll Nutr 1994;13:584-91.

Schenk BE, Festen HP, Kuipers EJ et al. Effect of short- and long-term treatment with omeprazole on the absorption and serum levels of cobalamin. Aliment Pharmacol Ther 1996;10:541-5.

Bradford GS, Taylor CT. Omeprazole and vitamin B12 deficiency. Ann Pharmacother 1999;33:641-3.

Bellou A, Aimone-Gastin I, De Korwin JD et al. Cobalamin deficiency with megaloblastic anaemia in one patient under long-term omeprazole therapy. J Intern Med 1996;240:161-4.

MESH Terms & Keywords

Vitamin B12 Deficiency, Proton Pump Inhibitor, Omeprazole, Prilosec, Macrocytic Anemia, Hyperhomocysteinemia, Neuropathy

Source: CONSULT Evidence-based Medicine

6 Replies
oldestnewest
phil

Thanks

A god article on PPis

Phil

Reply
starveycat

Help being 77 and thick as two planks. Having to take ppi because if acid reflux damaging my vocal chords and being a strict vegetarian do I need to take b12 supplements many thanks.

Reply
gutlesswonder

Hi starveycat,

Have you had any gastro-intestinal surgery?

Are you taking any medications for other medical conditions?

I look forward to your reply.

Reply
gutlesswonder

Many apologies -- I had overlooked not replying to you properly.

The excuse is that there are 8 different B vitamins and each is sufficiently different as to warrant it's own treatise - which defeated me!

Definitely as a strict vegetarian you should keep a very close watch on not becoming deficient, so supplementing is probably unavoidable. But equally you need to be as careful in not overdosing.

I have a regular diet, reasonably balanced, but take a complexed B group supplement at 150% NRV and have an occasional blood test.

Reply
starveycat

I have not had any surgery. I take levothyroxine for under active thyroid, fostair and salamol for asthma and gaviscon advance also omeprazole. I choose to take a multivitamin as well as D3 . I really do appreciate you taking your time to answer my query very many thanks

1 like
Reply

Thank you for this.

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