Oral vitamin B12 is in a crystalline form. It does not go through the normal processes involved in B12 absorption(eg intrinsic factor, R protein, etc). It is absorbed directly across the small intestinal mucosa.

PPIs reduce B12 absorption because acid is required to liberate B12 that is bound to food.

In my opinion, PPI frequently use most of population,but it is not guiltless. PPI caused B12 deficiency. Therefore if it is use long time, we can give patients suggestion of B12. PPI leaded to B12 deficiency is not clear. Probably, PPI caused to diminish gastric acid production. In my region (RIZE, TURKEY), We determine B12 deficiency for most of adult population (approximately one to third) I start to either b12 treatments or nutrition support for patients according to B12 levels.

A new study published in JAMA showed an association between gastric acid inhibition and B12 deficiency:

http://www.ncbi.nlm.nih.gov/pubmed/24327038

Although, systematic reviews showed similar efficacy of oral and intramuscular supplementation, these studies were not focused on patients using PPIs or those who underwent gastrectomy.

Thanks to both Erkan and Ali.

I suppose my question was about the exact biopharmacology of PPI. If PPIs do not inhibit gastric intrinsic factors, then I assume that oral Vitamin supplements will be absorbed effectively. If this is the case then there will be no need to consider intramuscular route of admistrationm which need physicians' prescriptions, unlike oral supplements which are available over the counter.

What I am trying to understand is this:

Is the artificially induced hypochlorhydria or achlorhydria by PPIs is exactly similar to the achlorhydria seen in atrophic and autoimmune gastritis in which there is total lack of intrinsic factors?

Once again, thank you.

Nice question ! Have a look at:

http://gut.bmj.com/content/26/6/594.full.pdf

http://www.ncbi.nlm.nih.gov/pubmed/2518851

http://www.ncbi.nlm.nih.gov/pubmed/1775933

it seems that PPIs do not affect intrinsic factors !

Thank you Ali.

These are very interesting papers. What is even more useful to discover is what the last paper indicates that whilst PPI do not inhibit Int Factors, H2receptor antagonists, Ranitidne, can actually impair IF release . Therefore oral vit b12 supplements may be less effective in patients taken Ranitidine in comparison to those receiving Esomeprazole, for example.

Thanks again

Hi,

I think, It is too early to say yes or no. According to the available data:

"Among the patients with the deficiency diagnosis (case patients), 3120 (12.0%) had been dispensed 2 or more years' supplies of PPIs, and 1087 (4.2%) had been dispensed 2 or more years' supplies of H2RAs with no PPI use. The rest (83.8%) did not take either medicine. These patients were mainly female (57.4%), 60 years old or older (67.2%), and non-Hispanic white (68.4%)".

Thus, with the available data, we cannot come up with the final conclusion that PPI can affect B12 absorption and lead to vitamin B12 deficiency.

Yes, you are absolutely right. Even the recent study itself indicated that there are so many confounders. Even in clinical practice, I am not aware of a sudden surge of anaemia and dementia in those who have been using long term PPI for GERD symptoms control (the largest PPI group user).

Could it be due to the relatively short half life of PPI and to the spare of Intr Factors that B12 def is not clinically prevalent in practice?

Also , what about the small cohort of patients who may combine PPI and H2RAs, due to the superior nocturnal acid suppression capacity that the H2RAs recognised for? Are they at greater risks?

Thanks .

PPIs do cause B12 deficiency . Clinical impression is no substitute for research! And oral supplementation is unlikely to help. However, intramuscular injection is unnecessary. Sublingual or intranasal B12 formulations are available, absorbed directly into the blood, and are well-absorbed.

What is the evidence that oral supplementations are unlikely to help?

In my personal experience PPIs do not affect the absorption of B12 vitamin. We always test PCA in the serum if case of B12 malabsorption and generally we perform OEGDS

I like the discussion on this topic. We don't have yes or no answers to these kind of clinical questions, only relentless research will help Physician to make appropriate clinical decision

As far as I know it the effect of PPIs on the gastric pH which reduces vitamin B12 absorption since a similar effect is produced by H2 blockers.like ranidine.

PPIs may reduce B12 absorption from natural food. This is because B12 in food is protein-bound. Gastric acid and pepsin are required to break the bond and liberate B12. The next crucial step is for the B12 to bind to intrinsic factors (IFs). Only then B12 will be absorbed.

My theory is : If B12 in modified or fortified supplements (unlike the one in natural food) was not protein bound, and if IFs are intact, then B12 can potentially be reliably absorbed in individuals on PPI therapy.

I agree with you, Ali Hussein. As long as suplements are not protein-bound and doesn't bind protein R, absortion should be normal.

On the other hand, ranitidine is less effective than PPI supressing acid secretion, so it's not surprising that PPIs more tendent to reduce B12 (from food) absortion than ranitidine.

PPI interfere with vitamin B12 absorption

Publised in medscape.com:

"Use of acid-inhibiting medications for 2 or more years may lead to vitamin B12 deficiency, especially among women and younger individuals who take stronger doses, according to a study published in the December 11 issue of JAMA.

Jameson R. Lam, MPH, from the Division of Research, Kaiser Permanente, Oakland, California, and colleagues conducted a case-control study involving the Kaiser Permanente Northern California adult patient population. They compared the electronic records of 25,956 patients with diagnoses of vitamin B12 deficiency between January 1997 and June 2011 with the records of 184,199 patients without the deficiency but matched for sex, region of home clinic, race/ethnicity, year of birth, and membership duration.

The researchers evaluated whether the long-term use of proton pump inhibitors (PPIs) or histamine 2 receptor antagonists (H2RAs) was associated with vitamin B12 deficiency. Vitamin B12 deficiency may lead to irreversible neurological damage and other complications if left untreated for a long period."

But several studies, have proved that high doses of B12 oral could be effective, partially absorbed, and parenteral via (im) may be avoided!

Another important question (see several Carmel's review, incluing a letter to editor published on NEJM) is wich is the normal B12 level and the best assay to diagnose B12 deficit!

More data about benefit of oral B12

But, some alert in case of Kidney disease!

Thank you.

To all:

?? When on PPIs, is there less intrinsic factor?

?? Is it the absence of a low pH that precludes attachment of the B12 to intrinsic factor?

Low pH is essential for liberating B12 from its bond with protein in food materials. However, oral B12 supplements and perhaps B12 in fortified cereals (if they are not protein bound) do not require acidic media to be freed.

Unlike pernicious anaemias, PPIs do not reduce intrinsic factors. This means that all forms of non- protein bound B12 in oral supplements , which do not require acidic pH to be freed, are in fact available to bind to the intact intrinsic factors.

Providing that the small bowel is intact with no bacterial overgrowth, this B12- intrinsic factor complex should be absorbed optimally in individuals taken PPIs

I agree with A. Hussein, and you may want to consider a B12 supplement that provides 100% of the RDA.

The simultaneous presence of H. pylori in the stomach and assumption of PPI is a condition at great riskk of glandular atrophy development and parietal cell dysfunction with a consequent deficiency in B12 vitamin absorption. This is stated even in European H. pylori Study Group Consensus of 2012 (attachment). An antigenic mimicry between bacterium and proton pump may be involved. Statement 13, evidence level 3b.

Oral vitamin B12 is in a crystalline form. It does not go through the normal processes involved in B12 absorption(eg intrinsic factor, R protein, etc). It is absorbed directly across the small intestinal mucosa.

PPIs reduce B12 absorption because acid is required to liberate B12 that is bound to food.

This is an interesting area of study

Taking proton pump inhibitors (PPIs) to ease the symptoms of excess stomach acid for more than two years was linked to a 65 percent increase in the risk of vitamin B-12 deficiency.Stomach acid is helpful in the absorption of B-12, Corley so it makes sense that taking medications that reduce the amount of stomach acid would decrease vitamin B-12 absorption.

Finally the answer we were waiting for your question. Here is a resume of the paper from Journal Watch:

SUMMARY AND COMMENT | GENERAL MEDICINE

January 2, 2014

Prolonged Gastric Acid Suppression and Vitamin B12 Deficiency

Allan S. Brett, MD Reviewing Lam JR et al., JAMA 2013 Dec 11; 310:2435

A large case-control study revealed excess risk for B12 deficiency among long-term users of proton-pump inhibitors.

In theory, prolonged suppression of gastric acid production could predispose patients to vitamin B12 deficiency; gastric acidity promotes extraction of B12 from food, allowing it to be absorbed after binding to intrinsic factor. This case-control study from the Kaiser system in California was designed to show whether proton-pump inhibitors (PPIs) and histamine-2–receptor antagonists (H2RAs) are associated with vitamin B12 deficiency.

Researchers compared 26,000 patients in whom B12 deficiency was diagnosed during a 15-year interval (cases) and 184,000 matched controls without this diagnosis. Cases were significantly more likely to have received ≥2 years of recent PPI therapy than were controls (12.0% vs. 7.2%). The association remained significant after adjustment for potential confounders (odds ratio, 1.65); a dose-response effect was noted. A significant but weaker association was noted between ≥2 years of H2RA therapy and B12 deficiency (OR, 1.25). To lend credence to these results, the researchers also noted a significant association between B12 deficiency and metformin use (which has been documented in other studies) but no association between B12 deficiency and several other drugs with no known relation to B12 deficiency.

COMMENT

Add vitamin B12 deficiency to the list of possible adverse effects associated with prolonged proton-pump inhibitor therapy. Although this study doesn't prove cause and effect, the mechanism is plausible. Clinicians should be vigilant for symptoms and laboratory abnormalities associated with B12 deficiency (e.g., neuropathy, macrocytosis) among long-term users of PPIs.

EDITOR DISCLOSURES AT TIME OF PUBLICATION

Disclosures for Allan S. Brett, MD at time of publication Nothing to disclose

CITATION(S):

1. Lam JR et al. Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency. JAMA 2013 Dec 11; 310:2435. (http://dx.doi.org/10.1001/jama.2013.280490)

At our clinical practice, we recommend in case of B12 functional deficit (B12 200-350), slight deficit (without gastric athrophy, negative PACA or intrinsic factor antibodies) or high level of homocystein we recommend high dose of B12 (hidroxycobalamin 1 mg; optovite) oral once a week during two or three months.

After analytical control, only a few amount of patient need to pass to parenteral (intramuscular) way

Thanks Jose. Are these patients on PPIs or any kind of gastric acid suppressors? or do they have other aetiology for their B12 deficiency (such as pernicious anaemia, short bowel, bacterial overgrowth, etc) ?

Thanks

In case of pernicious anemia, bariatric surgery, gaxtrectomy we usuallly begin with im,

In case of Helicobacter pylory, celiac disease (gluten intolerance) or bacterial overgrowth we send to gastroenterology to treat the cause, and temporally we begin with oral B12. It is unfrequently we need to pass to im

The rest of causes, PPIs, senil, vegans, etc we mostly need to recommend temporatly oral B12.

B12 high does is rather well absorbed in most of clinical situations

Thanks to you

Sorry, I forget.

In cases of inflammatory intestinal disease my collegues focus to treat the inflamation, give iv iron and give folic acid and b12 oral. unfrequently they need to pass to im.

In these few cases, we must rule out: helicobacter infection or/and hypothyroidism!

Wouldn't be nice to think about sublingual B12 tablets ?

Sorry, but I have not experience!

A conclusive question based on all the answers added to this very interesting question: what is the clinical implication of the phenomenon? Do you suggest in patients assuming long-term PPI to assay serum levels of B12 vitamin? At what interval of time di you suggest to repeat the investigation in the case of normal levels? Is it enogh the assay of B12 vitamin or are supplemental investigations needed (such as MCV or neurologic examination)? I think that the discussion must be focused to this aspect.

Yes, I entirely agree with you Leradi Enzo. Since it seems that there is a little doubt that acid suppressants reduce B12 absorption from food, at least in theory, further prospective studies are required to substantiate clinical significance of such findings.

Will it be appropriate and feasible to consider a baseline B12 level at the start of PPI therapy followed by another B12 serum level after 2-3 years while on therapy, in individuals expected from the beginning to be on long term PPIs (such as Zollinger Ellison syndrome, or patients with intractable reflux) ?

Alternatively, and perhaps for the time being, will it be worth considering oral vitamins and mineral supplements for individuals on long term PPIs ?

Dear Alì Hussein, you suggest a control of serum B12 levels after 2-3 years of prolonged PPI therapy and oral supplemetation in the case of deficiency. My doubts, in the absemce of evidence based protocols, concern the timing of follow-up (what do you believe about once in a year?) and oral supplementation in subjects who have a difficult absorrption. Would it be better a pareneral high dose administration? I think that it is the time of evaluating this aspect in controlled clinical trials.

I am agree with Enzo!

Check before begining. Then, at least once a year.

Add high dose of oral supplement, in case of decrease of B12 level, increase of homocystein level, increase of MVC or MPV (medium platelet volume)

But, please, do not forget to check iron levels, too.

A simultaneous administration of metformin must be evaluated too. The association PPI-metformin appears to be a strong inhibitor of vitanmin B12 absorption.

Of course!!!

I cannot see the justification for annual B12 assay. Remember that adults' liver can store several years' worth of B12 in reserve, thanks to the efficient enterohepatic circulation. It will probably take few years for B12 to be depleted. This is a multifactorial matter, depending on age, gender, co morbidities, drug history, initial B12 level and genetic factors.

Sorry, I have not experience in this aspect!

Do you think that theoretical bases of hepatic storage of B12 vitamin are enogh to suggest a clear guideline for the clinical practice? Since we have not controlled trials, how do you design a clinical study aimed to investigate a clear follow-up and the modelities of B12 supplementation in subjects with a deficiency? There is a lot of subjects who assume PPI for moe and more years not only for Zollinger Ellison or severe gastroesophageal reflux, but also for the chronic assumption of non steroidal anti-inflammatory drugs or simply in association to multi-drug treatments. So the clinical relevance of the problem needs a clear anwer for the pratictioner who has the responsability of the daily management of these patients. We must, moreover, remember that even patients with liver cirrhosis often assume PPI for tha presence of esophageal varices and congestive gastropathy. What about the B12 storage in these patients? And, finally, how does metformin increases the ability of PPIs to antagonize B12 absorption? Many subjects with insulin resistance or diabetes assume both metformin and PPIs.