Zinc Deficiency Anemia Associated with Proton Pump Inhibition
Authors: Hanson Zachary D , Hagele Adam , Borecky Michael , Fay Andrew , Mirshahidi Saied , Boghossain Raffi , Akhtari Mojtaba 
Published: December 2024

Background:
Proton pump inhibitors (PPI) are commonly prescribed medications that are well known to cause micronutrient deficiencies. PPIs have been linked to deficiencies in iron, vitamin B12, vitamin C, calcium, and magnesium due to disruption of the stomach's acidic environment. Recent studies have shown Zinc (Zn) deficiency may be a reversible cause of anemia in certain patient populations. Zn plays multiple roles in erythropoiesis including iron metabolism, heme synthesis, erythroid cell growth regulation, and erythropoietin signaling. Zn is not stored in large quantities in the body, so maintaining adequate intake is critical. One cause of acquired Zn deficiency may be medications that alter absorption, including PPIs. Dietary Zn dissolves into ionic Zn when exposed to the acidic environment of the stomach, where ionic Zn is absorbed throughout the intestine, with the jejunum having the highest rate of absorption of Zn. PPIs may play a role in Zn deficiency given the acid blocking effects in the stomach leading to poor Zn absorption.
This descriptive, retrospective study examined 61 patients who were taking PPIs within 3 months of Zn deficiency diagnosis. All patients were administered Zn replacement and PPI medications were stopped, changes in hemoglobin and plasma Zn concentration (pZc) were monitored over 12 months. This study was completed with a panel of patients from an academic outpatient hematology center in Southern California, United States of America.
Objectives:
Primary endpoints: determine the proportion of patients who will have anemia resolution after starting Zn replacement and PPI cessation. Secondary endpoints: determine if HGB concentration will increase over 12 months following replacement of Zn and cessation of PPI medications in patients with Zn deficiency and chronic anemia and determine the time to Zn deficiency resolution.
Methods:
Forty-eight patients with chronic anemia (HGB &lt;12 g/dL for women, HGB &lt;13 g/dL for men for &gt;3 months) over the age of 18 were identified to have Zn deficiency (pZc &lt;65 ug/dL) and were on PPI within three months of diagnosis of Zinc deficiency. Zinc Sulfate 220 (50)mg capsule was given daily, and PPI medications were discontinued.
A retrospective analysis was completed for prior medical history, lab data, and HGB was tabulated at the time markers of 1, 3, 6, and 12 months following initiation of Zn replacement. Collected data was analyzed with ANOVA and CHI-squared for response in all patients.
Results
Prior to Zn replacement and PPI cessation, the average HGB among patients was 9.6 g/dL, WBC was 6.8 x103/uL, MCV was 89.5 fl, PLTS were 224 x103/uL. Average pZc was 50.8 ug/dL.
Primary endpoint of anemia resolution was found in 23 of 48 patients (48%).
Following 1 month of Zn replacement, the average HGB was 9.9 g/dL (p = 0.31, n = 43) with pZc of 68 ug/dL (p = 9.2x10-6). The 3-month average HGB was 10.6 g/dL (p = 0.012, n = 39) with pZc of 67.9 ug/dL (p = 2.2x10-8). The 6-month average HGB was 11.7 g/dL (p= 5.7x10-7, n = 33), with pZc of 66.6 ug/dL (p = 4.9x10-6). The 12-month average HGB was 11.3 g/dL (p = 4.1x10-5, n = 28) with pZc of 61.5 ug/dL (p = 0.0015).
Conclusions:
Zn replacement and PPI cessation significantly improved HGB levels in patients with Zn deficiency and chronic anemia in patients who were on PPI, with resolution of anemia in 48% of patients. There was a statistically significant improvement from baseline HGB at the 3, 6, and 12-month time markers. Further prospective studies are warranted to determine the specific mechanism of Zn deficiency in anemia, as well as clinical studies determining zinc replacement dosing, monitoring, and toxicity.