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Gastric Acid Inhibitors And Iron Deficiency: Confirmed Association.



Numerous animal, as well as human clinical trials support the conclusion that the absorption of iron is markedly increased by gastric acidity. Several clinical conditions associated with achlorhydria/ hypochlorhydria (atrophic gastritis, pernicious anemia, gastric resections, vagotomy) have been shown to be associated with decreased iron absorption and/or iron-deficiency anemia. (Ito and Jensen 2010) According to that, it could be expected that the regular consumption of acid suppressing medicines also affects the absorption of iron, leading to iron deficiency-associated problems.
The most recent study conducted to verify this hypothesis was published in a well-known scientific journal; Gastroenterology, in March 2017. The article was titled “Proton Pump Inhibitor and Histamine-2 Receptor Antagonist Use and Iron Deficiency” and concluded that “gastric acid inhibitor use for ≥2 years was associated with an increased subsequent risk of iron deficiency…” (Lam, et al. 2017)
The original publication can be consulted in:
https://www.ncbi.nlm.nih.gov/pubmed/27890768
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This time, the authors conducted a community-based case-control study within the Kaiser Permanente, Northern California (KPNC) health care system. During the study, the association between acid suppressing medication use (Proton pump inhibitors PPIs and Histamine 2 receptors antagonists H2RAs) and the subsequent risk of iron deficiency was evaluated in 77.046 cases patients with new iron deficiency diagnoses (January 1999 – December 2013) and 398.314 controls.
Both, PPIs and H2RAs consumption for more than 2 years were associated with an increased subsequent risk for iron deficiency. The odds ratio was 2.49; 95% confidence interval, 2.35 – 2.64 for PPIs and 1.58; 95% CI, 1.46 – 1.71 for H2RAs, even excluding patients with pre-existing risk factors for iron deficiency.
Although this is not the only study conducted with the aim of verifying the association between the use of acid suppressing medicines and iron deficiency, it is one of the most conclusive because of the large number of patients involved; 77.064 cases and 398.314 controls, as well as the high odds ratio obtained; 2.49 for PPIs and 1.58 for H2RAs. An odds ratio of 2.49 for PPIs means that a person consuming PPIs for more than 2 years has a 249% higher risk of developing iron deficiency compared to another person not consuming PPIs.
Other recent studies highlighting the relationship between acid suppressing drugs and iron deficiency include:
(Boban, et al. 2016) published in the International Journal of Cardiology. This study involved 604 heart treatment patients, of whom 294 were using proton pump inhibitors; concluding that this type of drugs may affect red blood count indexes. The analysis revealed that patients taking proton pump inhibitors were six-times more likely to suffer from anemia.
(Shikata, et al. 2015) published in the Circulation Journal. In this study, the clinical characteristics of 278 outpatients who received blood test including complete blood count and serum creatinine concentration were analyzed. The frequency of anemia was 51% in patients receiving PPIs and 19% in those not receiving PPIs (chi-squared test, P<0.001). Among these patients, the change in hemoglobin (Hb) after the initiation of PPI in 36 patients within 1 year before and within 1 year after the initiation of PPI was also investigated. Mean decrease in Hb after the initiation of PPI was -0.38±0.87 g/dl (95% confidence interval: –0.67 to –0.09 g/dl).
(Sarzynski, et al. 2011) published in Digestive Diseases and Sciences. This study was a retrospective cohort of 98 adult patients who received PPI therapy for at least one year. The authors compared the change in hematologic indices among patients receiving PPI therapy with matched controls. All hematologic indices decreased significantly from baseline: hemoglobin (-0.19 g/dl), hematocrit (-0.63%) and mean corpuscular volume (-0.49 fL). After adjustment for confounders, the odds ratio of decreasing hemoglobin by 1.0 g/dL while on chronic PPI therapy was 5.03, while the odds ratio of decreasing hematocrit by 3% was 5.46 both significant at 0.001 level.
Multiple case reports also support the association between acid suppressing drugs and iron deficiency; for example:
(Dado, Loesch and Jaganathan 2017) published in Current Therapeutic Research. A 58-year-old man with an extensive cardiac history and gastroesophageal reflux disease on long-term omeprazole therapy presented with a non-ST-segment elevation myocardial infarction and was noted to be profoundly anemic with a hemoglobin level of 6.6 g/dL. This case emphasizes the need for improved awareness and future studies relating to the possible complications of long-term PPI use, including iron deficiency.
(Hashimoto, Matsuda and Chonan 2014) published in International medicine. A 59-year-old man, was referred to our hospital for a detailed examination due to iron-deficiency anemia. Rabeprazole was prescribed for reflux symptoms in January 2011, after which the patient gradually developed anemia and was prescribed ferrous sulfate and vitamin C in September 2011. However, the anemia did not improve, and he was referred to the hospital in March 2013.
There is an interesting fact in this last case report. Notice that even with iron supplementation, in the form of ferrous sulfate, the condition of anemia did not improve. This fact can be explained because the rate of absorption of non-heme iron is extremely poor without gastric acid, and it has long been known that iron absorption is poor under conditions of gastric acid deficiency, such as that observed in patients using rabeprazole or other PPIs.
This case shows that special considerations must be taken in account when iron supplements are going to be administered to patients treated with proton pump inhibitors. Not any iron salt is appropriate for these patients. Only iron salts whose absorption does not depend on the gastric acidity can be useful in this specific condition. This is the case of the heme iron polypeptide and ferrous bisglycinate.
References
Boban, Marko, Marinko Zulj, Viktor Persic, Igor Medvedc, Drazen Zekanovic, and Aleksandar Vcev. 2016. “Prolonged utilization of proton pumpinhibitors in patients with ischemic and valvular heart disease is associated with surgical treatments, weight loss and aggravates anemia.” International Journal of cardiology 219: 277–281. doi:http://dx.doi.org/10.1016/j.ijcard.2016.06.058.

Dado, David N., Erin B. Loesch, and Sudha P. Jaganathan. 2017. “A case of severe iron deficiency anemia associated with long-term proton pump inhibitor use.” Current therapeutic research, clinical and experimental 84: 1-3. doi:10.1016/j.curtheres.2017.01.003.
Hashimoto, Rintaro, Tomoki Matsuda, and Akimichi Chonan. 2014. “Iron-deficiency anemia caused by a proton pump inhibitor.” International medicine 53 (20): 2297-2299. doi:10.2169/internalmedicine.53.2743.

Ito, Tetsuhide, and Robert T. Jensen. 2010. “Association of long-term proton pump inhibitor therapy with bone fractures and effects on absorption of calcium, vitamin B12, iron, and magnesium.” Current gastroenterology reports 12 (6): 448–457. doi:10.1007/s11894-010-0141-0.
Lam, Jameson R., Jennifer L. Schneider, Charles P. Quesenberry, and Douglas A. Corley. 2017. “Proton pump inhibitor and histamine-2 receptor antagonist use and iron deficiency.” Gastroenterology 152 (4): 821-829. doi:10.1053/j.gastro.2016.11.023.

Sarzynski, E., C. Puttarajappa, Y. Xie, M. Grover, and H. Laird-Fick. 2011. “Association between proton pump inhibitor use and anemia: a retrospective cohort study.” Digestive diseases and sciences 56 (8): 2349-53. doi:10.1007/s10620-011-1589-y.

Shikata, T., N. Sasaki, M. Ueda, T. Kimura, K. Itohara, M. Sugahara, M. Fukui, E. Manabe, T. Masuyama, and T. Tsujino. 2015. “Use of proton pump inhibitors is associated with anemia in cardiovascular outpatients.” Circulation journal 79 (1): 193-200. doi:10.1253/circj.CJ-14-0582.

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