Download Increased Vitamin B12 Requirement Associated with Chronic Acid

Ambulatory Care
Increased Vitamin B12 Requirement Associated with Chronic
Acid Suppression Therapy
Rex W Force, Angela D Meeker, Paul S Cady, Vaughn L Culbertson, Wendy S Force, and Craig M Kelley
BACKGROUND: Assimilation of vitamin B12 from dietary sources requires gastric acid. By decreasing acid production, the proton pump
inhibitors (PPIs) and histamine2 (H2)-blockers may reduce vitamin B12 absorption.
OBJECTIVE:
To determine whether chronic acid suppression therapy is associated with the initiation of vitamin B12 supplementation,
we conducted a retrospective case–control study using a state-wide Medicaid population.
METHODS:
Case patients were identified as those who initiated vitamin B12 supplementation during the study period. Four control
patients were age- and gender-matched to each case. Patients (n = 109 844) with a paid claim between September 27, 1995, and
September 27, 1997, were eligible for inclusion. Chronic acid suppression therapy was defined as treatment with H2-blockers or PPIs
for ≥10 of the 12 months prior to the first vitamin B12 injection. Comparisons were made between the case and control groups
regarding exposure to chronic acid suppression therapy.
RESULTS: One hundred twenty-five cases were matched to 500 controls. Twenty-three patients (18.4%) had been exposed to
chronic acid suppression therapy compared with 55 (11.0%) of the control group (p = 0.025; OR 1.82; 95% CI 1.08 to 3.09).
CONCLUSIONS: Initiation of vitamin B12
supplementation was associated with chronic gastric acid suppression therapy.
KEY WORDS: gastric acid suppression, vitamin B12.
Ann Pharmacother 2003;37:490-3.
Published Online, 20 Feb 2003, www.theannals.com, DOI 10.1345/aph.1C037
itamin B deficiency is a relatively common disorder,
V
with estimates of 2–20% of elderly patients being deficient in this important nutrient. However, the disorder is
12
1-3
4
not regularly recognized. Populations at risk for vitamin
B12 deficiency include strict vegetarians, achlorhydric patients (i.e., caused by aging, HIV infection, gastric resection, vagotomy), and alcoholics. In addition, patients who
have atrophic gastritis or have undergone gastric resection
procedures may be at risk due to decreased gastric acid
production and a loss of parietal cells that produce intrinsic
factor, which is necessary for optimal vitamin B12 absorp-
Author information provided at the end of the text.
The Idaho Drug Utilization Review Program is funded by the State
of Idaho Department of Health and Welfare.
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tion. Patients with small bowel resection may also be at
risk because the vitamin B12 intrinsic factor complex is absorbed in the terminal ileum. Finally, some patients may
develop antibodies to intrinsic factor or parietal cells. The
presence of these antibodies then reduces absorptive capacity for vitamin B12.1,5 Most patients will not manifest
signs and symptoms of vitamin B12 deficiency until intake
has been absent for at least 3 years.
The histamine2 (H2)-receptor antagonists and proton
pump inhibitors (PPIs), used to reduce the production of
gastric acid, have a very good safety record. Attesting to
this record, several H2-blockers were recently released for
use as over-the-counter (OTC) products in the US. Many patients receive these prescription and OTC products chronically for gastroesophageal reflux disease, nonulcer dyspepsia,
prevention of ulcers from nonsteroidal antiinflammatory
2003 April, Volume 37
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Research Reports
drugs, and other indications. When used chronically at
treatment doses, the H2-blockers and PPIs may induce
states where the gastric pH is increased for long periods of
time.6,7 Acid and pepsin are required for vitamin B12 release from dietary protein sources, and deficiency may occur from failure to absorb protein-bound vitamin B12.8-10
PPIs and H2-blockers, by decreasing gastric acidity, may
prevent cleavage of vitamin B12 from its protein source,
thus reducing the bioavailability of food-bound vitamin
B12. These data have been inconsistent and somewhat controversial and are reviewed elsewhere.11
Researchers have recognized reduced bioavailability of
vitamin B12 as a potential adverse effect of these drugs and
recommended monitoring.1,11 One study found that chronic
use of PPIs decreased serum vitamin B12 concentrations in
patients with Zöllinger–Ellison syndrome.12 However, no
studies have specifically addressed whether chronic acidsuppressive therapies might contribute to the initiation of
treatment for vitamin B12 deficiency. Using a state Medicaid drug claims database, we set out to determine whether
there was an association between chronic use of H2-blockers or PPIs and the initiation of vitamin B12 supplementation.
Methods
Data were collected for this retrospective case–control study from the
State of Idaho Medicaid drug database managed by the Idaho Drug Utilization Review Program. All continuously enrolled Medicaid patients
with ≥1 claims processed between September 27, 1995, and September
27, 1997 (n = 109 844 patients), were eligible for inclusion. Cases were
defined as patients who received their first vitamin B12 injection during
September 27, 1996, to September 27, 1997. First vitamin B12 injection
was defined as an absence of a vitamin B12 injection in the preceding 12
months based on paid Medicaid claims. For each patient, enrollment in
Medicaid was verified for at least 12 months prior to the first vitamin B12
injection. Controls were continuously enrolled patients without a documented vitamin B12 injection. For each case, a list of eligible controls
was extracted from the database and matched on the basis of gender and
age (± 1 y of case’s birth date). Next, 4 controls were randomly selected
from the eligible list and matched to the appropriate case patient. An index date was defined as the date of the first vitamin B12 injection for the
case patient. The medications studied included cimetidine, famotidine,
nizatidine, ranitidine, lansoprazole, and omeprazole. Chronic acid-suppressive therapy was defined as ≥10 of 12 months of treatment with full
doses (i.e., omeprazole 20 mg/d, ranitidine 150 mg twice daily, or equivalent) of agents in the year prior to the index date. Ten of 12 months was
selected because this indicates a refill rate of about 80%, a generally accepted measure of patient compliance when working with large claims
databases.13 For each case patient and their 4 controls, the same 12month period was evaluated. The rates of exposure to chronic acid-suppressive therapy in the 12 months prior to the index date were compared
with χ2 analysis.
prior to their index date compared with 55 (11.0%) of the
control group (p = 0.025; OR 1.82; 95% CI 1.08 to 3.09).
In the case group, 11 patients received a single agent for
the entire study period and 12 received multiple agents for
acid suppression. In the control group, 28 patients received
a single agent for chronic acid suppression and 27 received
multiple agents during the study period (Table 1).
Discussion
Earlier studies have found that treatment with H2-blockers or PPIs may reduce the bioavailability of vitamin B12
from food sources.11 In our study, patients who initiated vitamin B12 injections were more likely to have received
chronic therapy with PPIs or H2-blockers compared with
age- and gender-matched controls. Initiation of vitamin B12
injections was used as a surrogate marker for vitamin B12
deficiency. These data suggest an association between
chronic acid suppression therapy and the need to treat vitamin B12 deficiency.
There are several limitations to our study. While useful
for epidemiologic research, our Medicaid database does
not provide information >3 years prior to the study period.
With a limited history of drug and diagnosis codes, the previous health status of the patients included is difficult to
determine. For example, we do not know the number of
patients with gastrectomy in either group. We did investigate all diagnosis codes in patients who received vitamin
B12 injections and chronic acid suppression therapy in the 3
years prior to the study. Most had gastroesophageal reflux
disease and none had had a gastrectomy. Although we
know that patients received up to 12 months of therapy
with PPIs or H2-blockers, we do not know their total duration of therapy. Since vitamin B12 deficiency usually manifests itself after several years of low or absent intake, it is
plausible to assume that acid-suppressive therapy would
need to continue for >12 months. We did not evaluate drug
therapy >12 months prior to the index date. The point at
which this interaction becomes clinically significant has
yet to be determined. In addition, we did not determine
Table 1. Number of Patients Receiving Each AcidSuppressive Agent ≥10 of 12 Months
Results
One hundred twenty-five patients received their first vitamin B12 injection during the study period. The case patients were matched to 500 controls. The mean age of the
study population was 71.2 ± 20.8 years (mean ± SD, median 79). Eighty-three percent were women.
In the case group, 23 patients (18.4%) received ≥10 of
12 months of therapy with H2-blockers or PPIs in the year
www.theannals.com
Drug
Cases (n = 125)
n (%)
Controls (n = 500)
n (%)
Famotidine only
Cimetidine only
Nizatidine only
Ranitidine only
Lansoprazole only
Omeprazole only
Multiple Agentsa
2 (1.6)
1 (0.8)
0
5 (4.0)
0
3 (2.4)
12 (9.6)
4 (0.8)
0
2 (0.4)
12 (2.4)
0
10 (2.0)
27 (5.4)
23
55
TOTAL
a
Most patients received several different agents over the 12 months
prior to the index date.
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491
RW Force et al.
whether the patients actually developed vitamin B12 deficiency. It should be noted that vitamin B12 concentrations
in the blood may not correlate well with anemia and neurologic sequelae; serum methylmalonate and homocysteine may be better tests for identifying the deficiency.1
Additionally, patients with chronic gastrointestinal conditions may be more likely to be screened for vitamin B12 deficiency. Our methodology did not offer controls for biases
related to the quality or consistency of care provided for
these patients. Recently, infection with Helicobacter pylori
has been associated with vitamin B12 deficiency. Kaptan et
al.14 found that H. pylori eradication in patients with vitamin B12 deficiency resulted in a resolution of their anemia.
We did not evaluate our patients for the presence of H. pylori infection.
Medicaid populations are predominantly female and of
lower socioeconomic status; thus, data derived herein may
not be generalizable to the population as a whole. In addition, we do not know the overall severity of illness of the
patients in the study. The distribution of acid-suppressive
therapies in the cases and controls was similar (Table 1),
indicating some measure of similarity between the populations. However, the study lacked the power to detect small
differences in drug utilization.
Data presented in abstract form demonstrated that elderly patients with vitamin B12 deficiency were 7 times more
likely to have used chronic acid-suppressive therapy than
patients with normal vitamin B12 concentrations.15 However, monitoring these patients is not routinely performed, as
vitamin B12 deficiency in patients on chronic acid-suppressive therapy is not a well-recognized adverse effect.
Summary
In this retrospective case–control study, patients initiating vitamin B12 therapy were more likely to be receiving
long-term acid suppression therapy. Patients presenting
with vitamin B12 deficiency should be questioned about
prescription or OTC use of these products. Systematic,
prospective evaluation of this adverse effect is needed. Until
definitive studies have been performed, clinicians should
monitor patients on chronic acid-suppressive therapy with
H2-blockers or PPIs for vitamin B12 deficiency. In addition,
patients with vitamin B12 deficiency and H. pylori infection
should be treated with an eradication regimen.
Rex W Force PharmD BCPS, Director of Special Studies, Idaho
Drug Utilization Review Program (IDURP); Associate Professor of
Family Medicine and Pharmacy Practice, Department of Family
Medicine, Idaho State University, Pocatello, ID
Angela D Meeker PharmD, at time of writing, PharmD Student,
College of Pharmacy, Idaho State University; now, Pharmacist,
McKenzie-Willamette Hospital, Springfield, OR
Paul S Cady PhD, Database Manager, IDURP; Associate Professor and Associate Dean, College of Pharmacy, Idaho State University
Vaughn L Culbertson PharmD, Project Director, IDURP; Professor and Chair, Department of Pharmacy Practice, Idaho State University
Wendy S Force BSPharm, Clinical Specialist, IDURP
Craig M Kelley BS, Computer Systems Manager, IDURP
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The Annals of Pharmacotherapy
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Reprints: Rex W Force PharmD BCPS, Department of Family
Medicine, Idaho State University, Campus Box 8357, Pocatello, ID
83209-8357, FAX 208/236-4818, E-mail [email protected]
References
1. Swain R. An update of vitamin B12 metabolism and deficiency states. J
Fam Pract 1995;41:595-600.
2. Yao Y, Yao S-L, Yao S-S, Yao G, Lou W. Prevalence of vitamin B12 deficiency among geriatric outpatients. J Fam Pract 1992;35:524-8.
3. Pennypacker LC, Allen RH, Kelly JP, Matthews LM, Grigsby J, Kaye
K, et al. High prevalence of cobalamin deficiency in elderly outpatients.
J Am Geriatr Soc 1992;40:1197-204.
4. Carmel R. Prevalence of undiagnosed pernicious anemia in the elderly.
Arch Intern Med 1996;156:1097-100.
5. Clementz GL, Schade SG. The spectrum of vitamin B12 deficiency. Am
Fam Physician 1990;41:150-62.
6. Langtry HD, Grant SM, Goa KL. Famotidine. An updated review of its
pharmacodynamic and pharmacokinetic properties, and therapeutic use
in peptic ulcer disease and other allied diseases. Drugs 1989;38:551-90.
7. Richardson P, Hawkey CJ, Stack WA. Proton pump inhibitors: pharmacology and rationale for use in gastrointestinal disorders. Drugs 1998;
56:307-35.
8. King C, Leigach J, Toskes P. Clinically significant vitamin B12 deficiency secondary to malabsorption of protein-bound vitamin B12. Dig Dis Sci
1979;24:397-402.
9. Doscherholmen A, McMahon J, Ripley D. Vitamin B12 assimilation
from chicken meat. Am J Clin Nutr 1978;31:825-30.
10. Streeter AM, Durajappah B, Boyle R, O’Neill BJ, Pheils MT. Malabsorption of vitamin B12 after vagotomy. Am J Surg 1974;128:340-3.
11. Force RW, Nahata MC. Effect of histamine H2-receptor antagonists on
vitamin B12 absorption. Ann Pharmacother 1992;26:1283-6.
12. Termanini B, Gibril F, Sutliff V, Yu F, Venzon D, Jensen R. Effect of
long-term gastric acid suppressive therapy on serum vitamin B12 levels in
patients with Zöllinger–Ellison syndrome. Am J Med 1998;104:422-30.
13. Powell KM, Edgern B. Failure of educational videotapes to improve
medication compliance in a health maintenance organization. Am J
Health Syst Pharm 1995;52:2196-9.
14. Kaptan K, Beyan C, Ural AU, Cetin T, Avcu F, Gulsen M, et al. Helicobacter pylori — is it a novel causative agent in vitamin B12 deficiency? Ann Intern Med 2000;160:1349-53.
15. Ruscin JM, Valuck RJ. Chronic gastric acid suppression and vitamin B12
deficiency in older adults (abstract). Pharmacotherapy 1998;18:431.
EXTRACTO
TRASFONDO: La asimilación de vitamina B12 de fuentes dietarias requiere
ácido gástrico. Por su efecto disminuyendo la producción de ácido
gástrico, los inhibidores de la bomba de protones (IBPs) y los
bloqueadores de los receptores H2 (BH2) pueden reducir la absorción de
vitamina B12. Para determinar si la supresión crónica de ácido está
asociada al inicio de suplementación con vitamina B12, se realizó un
estudio retrospectivo con control de caso utilizando una población de
Medicaid de un estado de Estados Unidos.
DISEÑO: Los pacientes de caso fueron identificados como aquellos que
iniciaron suplementación con vitamina B12 durante el período del estudio.
Se parearon 4 pacientes de acuerdo a edad y sexo como control para cada
caso. Pacientes (n = 109 844) con una reclamación de pago entre el 27 de
septiembre de 1995 y el 27 de septiembre de 1997 fueron elegibles para la
inclusión en el estudio. Se definió supresión crónica de ácido gástrico
como un tratamiento con IBPs o BH2 por ≥10 de los 12 meses antes de la
primera inyección de vitamina B12. Se compararon los grupos de casos y
controles en cuanto a la exposición a terapia de supresión crónica de ácido.
RESULTADOS: Ciento veinticinco casos se parearon con 500 controles.
Veintitrés de los 125 casos (18.4%) estuvieron expuestos a terapia
crónica de supresión de ácido comparado con 55/500 (11.0%) del grupo
control (p = 0.025, OR 1.82; 95% CI 1.08 a 3.09).
CONCLUSIONES: El inicio de suplementación de vitamina B12 se asoció a
la terapia crónica de supresión de ácido.
2003 April, Volume 37
Giselle Rivera-Miranda
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Research Reports
RÉSUMÉ
L’assimilation de la vitamine B12 d’origine
alimentaire requiert la présence d’acide gastrique. En diminuant la
production d’acide, les inhibiteurs de la pompe à protons et les
bloqueurs H2 peuvent réduire l’absorption de la vitamine B12. Afin de
déterminer si la suppression chronique de la production d’acide
gastrique est associée à l’initiation d’une thérapie de remplacement à
l’aide de vitamine B12, les auteurs ont conduit une étude rétrospective de
type cas-contrôle sur une population de bénéficiaires du régime
Medicaid de l’état.
MÉTHODOLOGIE: Les patients index sont ceux ayant initié un traitement à
l’aide de la vitamine B12 durant la période de l’étude. Quatre patients de
même âge et de même sexe ont servi de contrôles. Les patients (n =
109 844) ayant obtenu paiement pour une réclamation survenue entre le
27 septembre 1995 et le 27 septembre 1997 étaient éligibles pour
inclusion. La suppression chronique de la production d’acide gastrique
CONTEXTE ET OBJECTIF:
fut définie comme tout traitement avec un bloqueurs H2 ou un inhibiteur
de la pompe à protons utilisé pendant ≥10 des 12 mois avant la première
injection de vitamine B12. Des comparaisons furent faites entre les cas
index et le groupe contrôle en ce qui a trait à l’exposition à un traitement
de suppression chronique de la production d’acide gastrique.
RÉSULTATS: Au total, 125 cas index furent jumelés à 500 patients
contrôles. Vingt-trois des 125 cas (18.4%) furent exposés à un
traitement de suppression chronique de la production d’acide gastrique,
comparé à 55/500 (11.0%) dans le groupe contrôle (p = 0.025, OR 1.82;
IC 95% 1.08–3.09).
CONCLUSIONS: L’initiation d’un traitement de remplacement à l’aide de
vitamine B12 est associée à l’emploi de thérapie de suppression
chronique de la production d’acide gastrique.
Pierre Martineau
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