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Dig Dis Sci (2011) 56:23492353

DOI 10.1007/s10620-011-1589-y

ORIGINAL ARTICLE

Association Between Proton Pump Inhibitor Use and Anemia:


A Retrospective Cohort Study
Erin Sarzynski Chethan Puttarajappa
Yan Xie Madhusudan Grover Heather Laird-Fick

Received: 15 November 2010 / Accepted: 18 January 2011 / Published online: 12 February 2011
Springer Science+Business Media, LLC 2011

Abstract
Background Proton pump inhibitors (PPIs) are widely
prescribed to treat gastrointestinal diseases. However,
concerns have been raised regarding their long-term use.
Gastric acid suppression may decrease iron absorption, and
it remains uncertain whether iron-deficiency anemia may
result from chronic PPI therapy.
Aims We aimed to explore the association between
chronic PPI use and iron-deficiency anemia.
Methods We conducted a retrospective cohort study of
adult patients in an academic outpatient setting who
received PPI therapy for at least 1 year between January 1,
2004 and January 1, 2006. We compared the change in
This work originated from the Department of Medicine, Michigan
State University.
E. Sarzynski (&)  H. Laird-Fick
Department of Medicine, Michigan State University,
B-301 Clinical Center, East Lansing, MI 48824, USA
e-mail: erin.sarzynski@hc.msu.edu
H. Laird-Fick
e-mail: heather.lairdfick@hc.msu.edu
C. Puttarajappa
Department of Medicine, Renal-Electrolyte Division,
University of Pittsburgh, A919 Scaife Hall, 3550 Terrace Street,
Pittsburgh, PA 15261, USA
e-mail: drchethan81@gmail.com
Y. Xie
Center for Statistical Training and Consulting, Michigan State
University, 178 Giltner Hall, East Lansing, MI 48824, USA
e-mail: yxie@msu.edu
M. Grover
Division of Gastroenterology and Hepatology, Mayo Clinic,
200 First Street SW, Rochester, MN 55905, USA
e-mail: grover.madhusudan@mayo.edu

hematologic indices among patients receiving PPI therapy


for at least 1 year with matched controls.
Results Of the 98 patients on chronic PPI therapy who met
inclusion criteria, 35% had no documented indication for
such therapy. At baseline, demographics and hematologic
indices were similar between PPI-users and controls. Among
patients on PPI therapy, all hematologic indices decreased
from baseline, including hemoglobin (-0.19 g/dL, P =
0.03), hematocrit (-0.63%, P = 0.02), and mean corpuscular volume (-0.49 fL, P = 0.05). PPI users had significant
decreases in mean hemoglobin and hematocrit (P \ 0.01 for
both) compared with matched controls. After adjustment for
confounders, including rates of esophagogastroduodenoscopy, colonoscopy and remote cancer status, the odds ratio
of decreasing hemoglobin by 1.0 g/dL while on chronic PPI
therapy was 5.03 (95% CI, 1.7114.78, P \ 0.01), while the
odds ratio of decreasing hematocrit by 3% was 5.46 (95% CI,
1.6717.85, P \ 0.01).
Conclusions Among adult patients receiving chronic PPI
therapy, there is a significant decrease in hematologic
indices from baseline.
Keywords Proton pump inhibitor  Anemia 
Malabsorption  Iron deficiency

Introduction
Since their advent in the late 1980s, proton pump inhibitors
(PPIs) have become widely used for the treatment of many
upper gastrointestinal disorders, including gastroesophageal
reflux disease, peptic ulcer disease and stress ulcer prophylaxis. In 2009 in the United States alone, 119.4 million prescriptions for PPIs were dispensed totaling sales of $13.6
billion [1, 2]. Overutilization of PPIs is well documented [3].

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In one series of hospitalized patients, rates of PPI use


increased six-fold from admission to discharge, presumably
because of failure to discontinue PPIs started for stress ulcer
prophylaxis [4]. More recently, adverse effects of long-term
PPI therapy such as interactions with clopidogrel that affect
efficacy after acute coronary syndrome, risk for hip fracture,
and association with community-acquired pneumonia have
gained significant scientific and public attention [57]. In
May 2010, the U.S. Food and Drug Administration revised
the prescription and over-the-counter labels for PPIs to
include new safety information about a possible increased
risk of fractures of the hip, wrist, and spine [8]. Understanding the effects of chronic acid-suppression caused by
PPI therapy is of great clinical value.
In the normal physiologic state, gastric acid facilitates the
release of cyanocobalamin from its protein-bound form in the
diet, and several studies have demonstrated a link between
long-term PPI use and decreased cyanocobalamin absorption
[9, 10]. Gastric acid also facilitates absorption of dietary nonheme iron by converting it from a non-absorbable ferric form
to an absorbable ferrous form [11]. Hypochlorhydric states,
including vagotomy and partial gastrectomy, have been
associated with iron deficiency [1214].
While it seems intuitively possible that chronic PPI use
may reduce dietary iron absorption and lead to iron deficiency anemia, only a few studies have examined this
potential association, with conflicting results. In one study by
Koop and Bachem, patients on chronic omeprazole therapy
for refractory peptic ulcer disease did not develop decreased
serum iron or ferritin levels over a 4 year follow-up [15].
However, the study was small and baseline iron and ferritin
levels were not assessed. Similarly, patients with ZollingerEllison Syndrome receiving long-term PPI therapy did not
develop iron deficiency anemia or deplete their iron stores
[16]. More recently, Hutchinson et al. observed that chronic
use of PPIs in patients with hereditary hemochromatosis
suppressed dietary iron absorption and resulted in significantly fewer phlebotomies over time [17]. In a case report of
two patients with known iron-deficiency anemia who failed
oral iron replacement therapy while concurrently taking
PPIs, iron status improved once PPIs were discontinued [18].
Given the conflicting results and poor generalizability of
prior studies, we designed a retrospective cohort study to see
if the sustained use of PPIs leads to iron deficiency anemia in
adults seen in a primary care practice.

Methods
Study Design
We conducted a retrospective cohort study to determine
whether chronic PPI use is associated with development of

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iron deficiency anemia. We used the Michigan State University Health Team electronic medical record database to
identify study participants. This database is a computerized
medical record system of approximately 150,000 patients
cared for by general medicine, family medicine, pediatrics,
surgery, obstetrics and gynecology, and subspecialty clinics. The database is representative of the urban population
of Lansing, Michigan and surrounding suburban areas. The
electronic medical record contains patient demographics,
current and previous diagnoses classified by ICD-9 codes,
current and previous medications and dosages, hospitalization records, and sub-specialty consultation records. Our
study was approved by the Michigan State University
Institutional Review Board.
Study Cohort
We identified 1,700 adult (age 1880) patients who were
initiated on PPIs (including esomeprazole, lansoprazole,
omeprazole, pantoprazole, and rabeprazole) between January 1, 2004 and December 31, 2006 in one of our primary
care practices. Of these subjects, 1,140 had at least one
hemoglobin value documented in their chart. Subjects were
excluded because of co-morbidities known to cause anemia
as identified by ICD-9 codes in their problems lists (i.e.,
gastrointestinal bleeding, dysfunctional uterine bleeding,
chronic kidney disease, inherited hemoglobinopathies,
chronic anticoagulation with coumadin or low-molecular
weight heparin, hemolysis, vitamin B12 or folate deficiency,
pregnancy, or active cancer) (n = 261) or lack of hematologic studies drawn prior to and 1 year after initiation of PPI
therapy (n = 781). Some patients met several exclusion
criteria. The remaining 98 subjects (8.6%) composed the
eligible study cohort (Fig. 1). Using a random number
generator, age and sex-matched controls were identified
using the same inclusion and exclusion criteria.
Data Extraction
The primary exposure of interest was PPI use for more than
1 year. Duration and dose of medication, as well as changes in medications, were tabulated. Hematologic indices
(including hemoglobin, hematocrit, red blood cell count,
mean corpuscular volume, white blood cell count, and
platelet count) were recorded prior to and after at least
1 year of PPI therapy. Additional laboratory data, including ferritin and iron studies, were recorded if available. If
multiple hematologic indices were available, we recorded
those values in closest proximity to the first year of PPI
therapy. Dates of laboratory results were recorded in order
to assess the length of time between collection and initiation of PPI therapy.

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MSU HealthTeam
150,000 active patients

Inclusion Criteria
18-80 years old
PPI therapy 1 year
1 CBC documented in EMR

Table 1 Cohort characteristics and baseline hematologic indices


Variable

PPI users

Controls

P value

Age, mean (SD)

56.67 (12.40) 55.21 (12.73)

0.42

BMI, mean (SD)

30.47 (7.40)

0.30

29.45 (6.09)

Gender, n (%)

1,140 Subjects

Exclusion Criteria
Alternate reason for anemia (261)
Missing hematologic data (781)

Female

57 (58.16)

57 (58.16)

Male

41 (41.84)

41 (41.84)

Hgb (g/dL), mean (SD)

14.30 (1.33)

14.29 (1.13)

0.96

HCT (%), mean (SD)

42.04 (3.64)

41.83 (2.87)

0.23

MCV (fL), mean (SD)

90.03 (4.64)

89.24 (4.69)

0.66

NSAID use, n (%)

41 (41.84)

37 (37.76)

ASA use, n (%)

33 (33.67)

22 (22.45)

Clopidogrel use, n (%)


Documented EGD

6 (6.12)
34 (34.69)

3 (3.06)
2 (2.04)

Documented colonoscopy

40 (40.82)

25 (25.51)

0.03

4 (4.08)

0 (0.00)

0.12
1.00

PUD

98 Subjects
Fig. 1 Flow chart of study design

Statistical Analysis
We performed descriptive statistical analyses on baseline
demographics, as well as a list of potential confounders
that could bias any association between PPI use and anemia, including body mass index, medications (e.g., aspirin,
clopidogrel, non-steroidal anti-inflammatory drugs, and
oral iron replacement therapy), surgery during PPI therapy,
H. pylori status, rates of peptic ulcer disease (PUD),
hematuria, epistaxis, and results of endoscopic studies
(esophagogastroduodenoscopy and colonoscopy). A general linear model was used to compare the change in
hematologic indices from baseline between PPI users and
controls, with and without adjustment for identified confounders (variables with P B 0.05). Matched paired t-test
was used to compare the change in hematologic indices.
Univariate and multivariate logistic regression was used to
calculate the odds ratios (ORs) and 95% confidence intervals for changes in hematologic indices between PPI-users
and matched controls. Data analysis was implemented
using Statistical Analysis Software (SAS) version 9.2.

Results
There were 98 subjects who met inclusion criteria and 98
controls. Baseline hematologic indices and medication use
were similar for both groups (Table 1). Only one PPI-user
and two controls had serial ferritin levels; only one PPIuser and two controls had serial iron studies documented in
their charts, and therefore these data are not reported. Rates

1.00

0.67
0.11
0.50
\0.01

Epistaxis

0 (0.00)

0 (0.00)

Hematuria

3 (3.06)

0 (0.00)

0.25

H. pylori

2 (2.04)

0 (0.00)

0.50

History of cancer

14 (14.29)

5 (5.10)

0.05

Documented bleeding event

0 (0.00)

1 (1.02)

1.00

Iron supplementation

3 (3.06)

2 (2.04)

1.00

BMI body mass index, Hgb hemoglobin, HCT hematocrit, MCV mean
corpuscular volume, NSAID non-steroidal anti-inflammatory drug,
ASA aspirin, EGD esophagogastroduodenoscopy, PUD peptic ulcer
disease

of aspirin and NSAID use were similar between PPI-users


and controls (P = 0.11 and P = 0.67, respectively). Similarly, clopidogrel use was not significantly different
between PPI-users and controls (P = 0.50, Table 1). Rates
of documented PUD, epistaxis, hematuria, and H. pylori
infection were rare and not significantly different among
PPI-users and controls (Table 1). However, documented
endoscopic procedures, including EGD and colonoscopy,
were significantly higher among PPI-users than non-users
(Table 1), and therefore these confounders were adjusted
for in the odds ratio calculation.
On average, hematologic indices were collected
6.63 months prior to and 20.16 months after commencing
PPI therapy. For controls, the two comparison hematologic
indices were drawn on average 24.3 months apart. Of the
patients receiving chronic PPI therapy, only 65% had a
clearly documented indication in their problem list. Among
PPI-users, 34.7% used omeprazole, 32.7% esomeprazole,
15.3% lansoprazole, 13.3% pantoprazole, and 4.1% rabeprazole (Table 2).
Among patients on PPI therapy, all hematologic indices decreased from baseline, including hemoglobin
(-0.19 g/dL, SE 0.09, P = 0.03), hematocrit (-0.63%,
SE 0.27, P = 0.02), and mean corpuscular volume
(-0.49 fL, SE 0.25, P = 0.05), while those for controls

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Table 2 Proton pump inhibitor (PPI) use by brand


Brand of PPI

Percentage

Omeprazole

34.7

Esomeprazole

32.7

Lansoprazole

15.3

Pantoprazole

13.3

Rabeprazole

4.1

Discussion

1
0.8

PPI-users

Controls
0.56

Change from Baseline

0.6
0.4

0.23

0.2
0.2
0

-0.2

-0.19

-0.4
-0.6

-1

-0.49

-0.63

-0.8
Hgb (g/dL)

HCT (%)

3% was 5.46 (95% CI, 1.6717.85). The odds ratio of


decreasing mean corpuscular volume by 2 fL was 2.49
(95% CI, 1.205.17), yet after adjusting for confounders,
this change was no longer significant.

MCV (fL)

Hematologic Index
Fig. 2 Change in hematologic indices ( SEM) in patients before
and after initiating proton pump inhibitor (PPI) therapy, compared
with patients not receiving PPI therapy. SEM standard error of mean

did not (Fig. 2). Compared with controls, PPI users had
significant decreases in mean hemoglobin and hematocrit
(P \ 0.01 for both), and this effect persisted after controlling for confounders (Fig. 2).
Among PPI-users, 21 subjects (21.4%) had a decrease in
their hemoglobin [1.0 g/dL while on therapy for more
than a year (Table 3). The adjusted odds ratio (OR) for a
1.0 g/dl decrease was 5.03 (95% CI, 1.7114.78). Similarly, the adjusted odds ratio of decreasing hematocrit by

We found a significant decrease in both hemoglobin and


hematocrit in patients taking PPIs for more than 1 year,
compared with age- and sex-matched controls, even after
controlling for potential confounders. The changes we
detected exceeded one standard deviation of the mean for
our regional laboratory. More than 20% of subjects had a
clinically significant decrease (hemoglobin C 1.0 g/dL
and/or hematocrit C 3%) after receiving PPI therapy for at
least 1 year. Given the widespread use of PPIs, even a
modest increase in adverse events such as anemia could
have significant clinical and economic implications. To our
knowledge, this is the first study to systematically evaluate
hematologic indices of patients on chronic PPI therapy.
Our study utilized a primary care population of urban
and suburban subjects, thereby increasing the generalizability of our results. Hematologic indices available
through the electronic medical record are comprehensive,
as automatic electronic updates link the medical record
with regional laboratories. We stringently applied exclusion criteria to limit confounding, and adjusted for potential confounders in our odds ratio analyses.
Our study limitations stem primarily from its retrospective design and small sample size. We attempted to
balance the exclusion of subjects for potential confounders
with the need for adequate sample size. We included
subjects using aspirin, clopidogrel, and NSAIDs, despite
the associated risk for occult gastrointestinal blood loss,
and then compared the rate of use between groups.
Although rates of ASA, NSAIDs, and clopidogrel use

Table 3 Odds ratios of decreasing hematologic indices after 1 year of proton pump inhibitor (PPI) therapy, before and after adjusting for
confounders (rates of EGD, colonoscopy, and remote cancer status)
Hematologic index

Group

OR (95% CI)
Unadjusted data

OR (95% CI)
Adjusted data

Hgb decrease [1 g/dL

PPI-users

21

5.07 (1.8314.08)

\0.01

5.03 (1.7114.78)

\0.01

Controls

5
5.29 (1.7216.27)

\0.01

5.46 (1.6717.85)

\0.01

HCT decrease [3%


MCV decrease [2 fL

PPI-users

18

Controls

PPI-users

27

Controls

13

2.49 (1.205.17)

0.02

1.77 (0.774.05)

0.18

Hgb hemoglobin, HCT hematocrit, MCV mean corpuscular volume, EGD esophagogastroduodenoscopy, OR odds ratio, CI confidence interval

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were slightly higher among PPI-users than controls, the


differences were not statistically significant. Despite this
strategy, our sample size was still small. Many potential
subjects were eliminated because they did not have blood
counts drawn prior to and 1 year after initiation of PPI
therapy (n = 781 of 1,140 potential subjects).
Other potential confounders, including over-the-counter
medications such as H2 blockers, antacids, and vitamins
were difficult to assess because of inconsistent documentation in the EMR. We did not collect data on use of other
prescription drugs that may alter gastric pH or decrease
platelet aggregation, such as sucralfate or selective serotonin reuptake inhibitors. Similarly, we were unable to
assess subjects medication adherence or dietary iron
consumption. Therefore we cannot exclude a non-random
distribution of these characteristics between the two
groups. Another pertinent limitation is that menstrual
blood loss is inconsistently documented in the EMR.
Therefore we excluded female patients with a history of
excessive menstrual blood loss (as documented in their
problem lists, ICD-9 code 626.X) and used age- and sexmatched controls to minimize this potential confounder.
Lastly, our data does not confirm iron deficiency as the
cause for the observed decline in hematologic values, and
serial ferritin levels were available for only a few subjects.
The trend of decreasing MCV for PPI-users and the pathophysiologic mechanisms for impaired iron absorption
suggests but does not confirm this condition [11, 19].
Despite the limitations of our study, we feel our results
warrant attention and provide an impetus for additional
studies. A larger prospective study could include additional
variables (ferritin levels, over-the-counter medication use,
documentation of menstrual blood loss, and medication
adherence, etc.), ensure availability of measures for all
subjects, and include a longer observation period to confirm or refute our findings.
Although PPIs have revolutionized the management of
many gastrointestinal disorders, there is growing concern
about the potential adverse effects associated with the
chronic use of these medications. Several review articles
highlight these concerns [20, 21]. Our results demonstrate
that anemia may be another potential consequence of
chronic PPI therapy. In our study of adult patients receiving
chronic PPI therapy, we found a significant decrease in
hemoglobin and hematocrit levels. The widespread use of
PPIs warrants further exploration to determine if irondeficiency anemia may result from chronic PPI therapy.
Acknowledgments We are grateful to Adriano Tonelli, MD for
providing the inspiration for this research. We also thank Abhimanyu
Beri, MD and Sahibzada Usman Latif, MD for their critical review of
the manuscript.
Conflict of interest

None reported for any authors.

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References
1. IMS Health Report. 2009 top therapeutic classes by US dispensed
prescriptions. Available at: http://www.imshealth.com/deployed
files/imshealth/Global/Content/StaticFile/Top_Line_Data/Top%20
Therapy%20Classes%20by%20U.S.RXs.pdf. Accessed 9 June
2010.
2. IMS Health Report. 2009 top therapeutic classes by US sales.
Available at: http://www.imshealth.com/deployedfiles/imshealth/
Global/Content/StaticFile/Top_Line_Data/Top%20Therapy%20
Classes%20by%20U.S.Sales.pdf. Accessed 9 June 2010.
3. Heidelbaugh J, Goldberg K, Inadomi J. Overutilization of proton
pump inhibitors: A review of cost-effectiveness and risk in ppi.
Am J Gastroenterol. 2009;104:S27S32.
4. Pham C, Regal R, Bostwick T, Knauf K. Acid suppressive
therapy use on an inpatient internal medicine service. Ann
Pharmacotherapy. 2006;40:12611266.
5. Ho P, Maddox T, Wang L, et al. Risk of adverse outcomes associated
with concomitant use of clopidogrel and proton pump inhibitors
following acute coronary syndrome. JAMA. 2009;301:937944.
6. Yang Y, Lewis J, Epstein S, Metz D. Long-term proton pump
inhibitor therapy and risk of hip fracture. JAMA. 2006;296:
29472953.
7. Gulmez S, Holm A, Frederiksen H, Jensen T, Pedersen C, Hallas
J. Use of proton pump inhibitors and the risk of communityacquired pneumonia: A population-based case-control study.
Arch Intern Med. 2007;167:950955.
8. FDA drug safety communication: Possible increased risk of fractures of the hip, wrist, and spine with the use of proton pump
inhibitors, 2010. Available at: http://www.fda.gov/Drugs/Drug
Safety/PostmarketDrugSafetyInformationforPatientsandProviders/
ucm213206.htm. Accessed May 25, 2010.
9. Koop H. Review article: metabolic consequences of long-term
inhibition of acid secretion by omeprazole. Aliment Pharmacol
Ther. 1992;6:399406.
10. Marcuard S, Albernaz L, Khazanie P. Omeprazole therapy causes
malabsorption of cyanocobalamin (vitamin b12). Ann Intern Med.
1994;120:211215.
11. Bezwoda W, Charlton R, Bothwell T, et al. The importance of
gastric hydrochloric acid in the absorption of nonheme food iron.
J Clin Gastroenterol. 2000;30:2933.
12. Cook J, Brown G, Valberg L. The effect of achylia gastric on iron
absorption. J Clin Invest. 1964;43:11851191.
13. Hines J, Hoffbrand A, Mollin D. The hematologic complications
following partial gastrectomy. Am J Med. 1967;43:555569.
14. Wheldon E, Venables C, Johnston I. Late metabolic sequelae of
vagotomy and gastroenterostomy. Lancet. 1970;i:437440.
15. Koop H, Bachem M. Serum iron, ferritin, and vitamin b12 during
prolonged omeprazole therapy. J Clin Gastroenterol. 1992;14:
288292.
16. Stewart C, Termanini B, Sutliff V, et al. Iron absorption in patient
with zollinger-ellison syndrome treated with long-term gastric
antisecretory therapy. Aliment Pharmacol Ther. 1998;12:8398.
17. Hutchinson C, Geissler C, Powell J, Bomford A. Proton pump
inhibitors suppress absorption of dietary non-haem iron in
hereditary haemochromatosis. Gut. 2007;56:12911295.
18. Sharma V, Brannon M, Carloss E. Effect of omeprazole on oral
iron replacement in patients with iron deficiency anemia. South
Med J. 2004;97:887889.
19. Schade S, Cohen R, Conrad M. Effect of hydrochloric acid on
iron absorption. N Eng J Med. 1968;279:672674.
20. Ali T, Roberts D, Tierney W. Long-term safety concerns with
proton pump inhibitors. Am J Med. 2009;122:896903.
21. Nealis T, Howden C. Is there a dark side to long-term proton
pump inhibitor therapy? Am J Therapeutics. 2008;15:536542.

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