Do PPIs suppress B12?

This letter to the Editor was published in the November 2001 issue of Parkhurst Exchange, p7


In the June 2001 issure of Parkhurst Exchange, your consultant AS
reported no serious side effects from the longterm use of pantoprazole,
to his knowledge.

Gastric acid suppressive therapy in general has been shown to suppress
the absorption of vitamin B12 from food, because the release of B12 from
food proteins requires the presence of gastric acid. Thus longterm use
of proton pump inhibitors such as omeprazole and probably pantoprazole
may lead to vitamin B12 deficiency, which can have serious and
potentially irreversible neurologic consequences, in addition to
hematologic and gastrointestinal problems.

I would suggest that any individual on medication which suppresses
gastric acid production also take a daily vitamin supplement containing
synthetic vitamin B12.


1. Bradford GS, Taylor CT. Omeprazole and vitamin B12 deficiency.
Annals of Pharmacotherapy 1999;33(5):641-3.
Abstract: The mainstay for cobalamin deficiency is correction of the
underlying disorder and replacement therapy. Because the defect is often
one of absorption, parenteral or intranasal routes are recommended. In
most cases, replacement therapy is all that is needed. The vitamin
preparation most commonly used is cyanocobalamin (also called vitamin
B12), which has no known physiologic role but instead is converted to a
biologically active form before it can be used by tissues. The studies
reviewed in this article clearly show that omeprazole therapy will
decrease the absorption of vitamin B12 by preventing its cleavage from
dietary proteins. However, these data are insufficient to infer that
clinically significant deficiency will occur over time. In fact, some of
the studies suggest that the simple addition of juices or other acidic
drinks into the diet may dramatically increase cobalamin absorption.
Clearly, well-designed clinical trials are needed to evaluate this
theory over an extended follow-up period to determine the clinical
significance of omeprazole-associated vitamin B12 deficiency and
possibly identify patients at risk for deficiency. In conclusion, the
possibility of dietary vitamin B12 malabsorption should be considered in
patients receiving chronic omeprazole treatment and presenting with
signs and symptoms of deficiency. All healthcare workers should be made
aware of the potential clinical complications of omeprazole-associated
vitamin B12 deficiency since it may go unrecognized and is easily
corrected. This is particularly relevant for elderly patients with poor
dietary intake of vitamin B12, impaired vitamin B12 stores, and certain
gastrointestinal disorders.

2. Termanini B, Gibril F, Sutliff VE, et al. Effect of long-term gastric
acid suppressive therapy on serum vitamin B12 levels in patients with
Zollinger-Ellison syndrome. Am. J. Med. 1998;104(5):422-30.
Abstract: BACKGROUND AND AIMS: Long-term treatment with H(+)-K(+)-
adenotriphosphatase (ATPase) inhibitors, such as omeprazole or
lansoprazole, for severe gastroesophageal reflux disease is now widely
used. Whether such treatment will result in vitamin B12 deficiency is
controversial. We studied whether long-term treatment with omeprazole
alters serum vitamin B12 levels in patients with Zollinger-Ellison
syndrome. METHODS: In 131 consecutive patients treated with either
omeprazole (n = 111) or histamine H2-receptor antagonists (n = 20),
serum vitamin B12 and folate levels and complete blood counts were
determined after acid secretion had been controlled for at least 6
months. These studies were repeated yearly. Serum vitamin B12 and folate
levels were correlated with the type of antisecretory drug and the
extent of inhibition of acid secretion. RESULTS: The mean duration of
omeprazole treatment was 4.5 years, and for H2-receptor antagonists 10
years. Vitamin B12 levels, but not serum folate levels or any
hematological parameter, were significantly (P = 0.03) lower in patients
treated with omeprazole, especially those with omeprazole- induced
sustained hyposecretion (P = 0.0014) or complete achlorhydria (P
0.0001). In 68 patients with two determinations at least 5 years apart,
vitamin B12 levels decreased significantly (30%; P = 0.001) only in
patients rendered achlorhydric. The duration of omeprazole treatment was
inversely correlated with vitamin B12 levels (P = 0.013), but not folate
levels. Eight patients (6%) developed subnormal B12 levels during
follow-up. CONCLUSIONS: Long-term omeprazole treatment leads to
significant decreases in serum vitamin B12 but not folate levels. These
results suggest patients with Zollinger-Ellison syndrome treated with
H(+)-K(+)-ATPase inhibitors should have serum vitamin B12 levels
monitored. Furthermore, these results raise the possibility that other
patients treated chronically with H(+)-K(+)-ATPase inhibitors may
develop B12 deficiency.

3. Thorens J, Froehlich F, Schwizer W, et al. Bacterial overgrowth
during treatment with omeprazole compared with cimetidine: a prospective
randomised double blind study. Gut 1996;39(1):54-9.
Abstract: BACKGROUND: Gastric and duodenal bacterial overgrowth
frequently occurs in conditions where diminished acid secretion is
present. Omeprazole inhibits acid secretion more effectively than
cimetidine and might therefore more frequently cause bacterial
overgrowth. AIM: This controlled prospective study compared the
incidence of gastric and duodenal bacterial overgrowth in patients
treated with omeprazole or cimetidine. METHODS: 47 outpatients with
peptic disease were randomly assigned to a four week treatment regimen
with omeprazole 20 mg or cimetidine 800 mg daily. Gastric and duodenal
juice were obtained during upper gastrointestinal endoscopy and plated
for anaerobic and aerobic organisms. RESULTS: Bacterial overgrowth (> or
= 10(5) cfu/ml) was present in 53% of the patients receiving omeprazole
and in 17% receiving cimetidine (p 0.05). The mean (SEM) number of
gastric and duodenal bacterial counts was 6.0 (0.2) and 5.0 (0.2)
respectively in the omeprazole group and 4.0 (0.2) and 4.0 (0.1) in the
cimetidine group (p 0.001 and 0.01; respectively). Faecal type bacteria
were found in 30% of the patients with bacterial overgrowth. Basal
gastric pH was higher in patients treated with omeprazole compared with
cimetidine (4.2 (0.5) versus 2.0 (0.2); p 0.001) and in patients with
bacterial overgrowth compared with those without bacterial overgrowth
(5.1 (0.6) versus 2.0 (0.1); p 0.0001). The nitrate, nitrite, and
nitrosamine values in gastric juice did not increase after treatment
with either cimetidine or omeprazole. Serum concentrations of vitamin
B12, beta carotene, and albumin were similar before and after treatment
with both drugs. CONCLUSIONS: These results show that the incidence of
gastric and duodenal bacterial overgrowth is considerably higher in
patients treated with omeprazole compared with cimetidine. This can be
explained by more pronounced inhibition of gastric acid secretion. No
patient developed signs of malabsorption or an increase of N-nitroso
compounds. The clinical significance of these findings needs to be
assessed in studies with long-term treatment with omeprazole, in
particular in patients belonging to high risk groups such as HIV
infected and intensive care units patients.

4. Batzri S, Brugada O, Harmon JW, Rich NM. Inhibition of acid secretion
in guinea pigs by tricyclic antidepressants: comparison with ranitidine
and omeprazole. J. Pharmacol. Exp. Ther. 1988;246(2):493-9.
Abstract: The antisecretory properties of imipramine on gastric
secretion in guinea pig in comparison with other antisecretory agents
was determined. In awake guinea pigs s.c. infusion of histamine (30
micrograms/kg/hr) increased acid and fluid secretion by 3- to 4-fold.
When acid output peaked, a bolus administration of the tricyclic anti-
depressant imipramine inhibited acid and fluid secretion. Imipramine and
other agents, such as ranitidine and omeprazole, inhibited gastric
secretion in a dose-dependent fashion. The most potent was the H2-
antagonist ranitidine (IC50, 0.2-0.3 mumol/kg), followed by the gastric
H-K-adenosine triphosphatase inhibitor, omeprazole (IC50, 0.5-0.6
mumol/kg). Imipramine (IC50 1-2 mumol/kg) was the least potent of the
inhibitors. Both ranitidine and omeprazole could abolish acid secretion,
but maximal inhibition with imipramine was 60% of initial. Promethazine
(25 mumol/kg), an H1 antagonist, and atropine (12 mumol/kg), a
muscarinic antagonist, inhibited gastric secretion by 40 to 50%.
Imipramine and atropine also inhibited basal acid secretion. In
dispersed gastric cells comparison between imipramine and omeprazole
showed that imipramine was about 5-fold more potent than omeprazole in
blocking histamine or dibutyryl cyclic AMP stimulation of aminopyrine
accumulation. Imipramine probably acts as a protonophore by increasing
the rate of proton-gradient dissipation rather than by interfering with
the hydrogen-pump system because, in gastric membranes, imipramine was
20-fold less potent than omeprazole in inhibiting the gastric H-K-
adenosine triphosphatase activity. These results suggest that imipramine
administered s.c. in guinea pigs is a potent antisecretory drug. Its
action may be due to a combination of anticholinergic and antihistamine
H2 activities.

5. Saltzman JR, Kemp JA, Golner BB, et al. Effect of hypochlorhydria due
to omeprazole treatment or atrophic gastritis on protein-bound vitamin
B12 absorption [see comments]. J. Am. Coll. Nutr. 1994;13(6):584-91.
Abstract: OBJECTIVE: To investigate the effects of hypochlorhydria and
acidic drink ingestion on protein-bound vitamin B12 absorption in
elderly subjects. METHODS: Absorption of protein-bound vitamin B12 was
examined in elderly normal subjects (n = 8), and in hypochlorhydric
subjects due to omeprazole treatment (n = 8) or with atrophic gastritis
(n = 3). Subjects underwent absorption tests of protein-bound vitamin
B12 ingested with water, cranberry juice and 0.1 N hydrochloric acid.
RESULTS: Protein-bound vitamin B12 absorption was lower in the
omeprazole-treated group (0.50%) compared to the normal group (1.21%; p
0.001). With cranberry juice ingestion, the omeprazole-treated group
showed an increase in absorbed protein-bound vitamin B12 (p = 0.025).
With dilute hydrochloric acid ingestion, there was a further increase in
vitamin B12 absorption (p 0.001). CONCLUSION: Omeprazole causes
protein-bound vitamin B12 malabsorption, and ingestion of an acidic
drink improves protein-bound vitamin B12 absorption.

Henry Olders, MD, FRCPC
SMBD – Jewish General Hospital, 5 East
3755 Cote Saint Catherine
Montreal, Quebec H3T 1E2

514-340-8222 x5881

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