Iron Deficiency Anemia Caused By Malabsorption from Proton Pump Inhibition
Authors: Boxer Michael 
Published: February 2020

Introduction:
Iron deficiency anemia (IDA) not responding to oral iron replacement usually requires a hematologic evaluation. 48 patients taking a proton pump inhibitor (PPI) and not responding to oral iron replacement were found to have an elevated serum gastrin (SG). No patient had gastrointestinal bleeding, gastric resection, bariatric surgery, or menorrhagia. Other causes for iron malabsorption such as celiac disease or helicobacter infection were not present. 94 percent responded to intravenous iron (IV iron).
Methods:
All patients previously had undergone diagnostic gastrointestinal evaluations. Testing for celiac disease and helicobacter infection was negative. Gastric biopsies did not demonstrate atrophy. Most referrals were from gastroenterologists.
Results:
94% responded to IV iron with a rise in their hemoglobin of &gt;/= 2 grams per cent. 83 percent (40/48) were women. Iron dextran (ID) at a fixed dose of 825 mgm was given to 85% of the patients. Twelve of these 41 patients were given a second infusion of ID as the first dose did not produce a satisfactory response. Ferric carboxymaltose and ferumoxytol were each given once at the fixed recommended dose, and second infusions was not necessary. Four patients received iron sucrose at a weight based dose, and a second series of infusions were not necessary. One patient responded to ferumoxytol after a suboptimal response to iron dextran.
An elevated SG was defined as &gt;100 pg/mL. The average SG was 370.25 pg/mL (114 to 2101 pg/mL).
Hemoglobin rose an average of 3.35 gram% (9.56 to 12.91 gm%). The change in hemoglobin was minus 0.4 to plus 7.0 gm% with a baseline hemoglobin ranging between 6.6 to 14.3 gm% and rising between 9.3 to 16.2 gram%.
Ferritin rose an average of 14.8 to 158 ng/mL with baseline ferritin ranging between 3 to 73 ng/mL and rising between 22 to 659 ng/mL
The average MCV rose from 75.89 to 84.93 fL with baseline MCV ranging between 61 to 93 fL rising between 69 to 96 fL
The average iron saturation rose from 7.49 to 22.89% with baseline saturation ranging between 2 to 34% and rising between 10 to 39%.
Discussion:
Dietary iron consists of both heme and non heme iron. Heme iron is derived from the hemoglobin and myoglobin in animal food sources such as meat, seafood, and poultry. Heme iron is in the ferrous (II) oxidation state, is easily absorbable, and contributes 10% or somewhat more of total absorbed iron. Non heme iron is in the ferric (III) form and is derived from plants and iron fortified food. Normally 1-2 mgm of iron is absorbed daily. Heme iron is well absorbed after its release by pancreatic enzymes. Non heme iron is less well absorbed and requires acid secretion from gastric parietal cells for the denaturing of ingested proteins and subsequent proteolysis. PPI causes decreased hydrogen ion (H+) production by inhibiting the hydrogen/potassium pump within gastric parietal cells. The elevated SG derives from G cell hyperplasia as a response to the lowered H+ activity caused by PPI. The decreased H+ activity inhibits the release of ferric iron from non animal sources. Iron absorption occurs in the proximal duodenum through the action of a brush border ferrireductase such as duodenal cytochrome B which reduces ferric iron to ferrous iron. With less ferric iron available for reduction less ferrous iron is absorbed, and iron deficiency results.
Intravenous iron fully corrected the IDA in 94% of treated patients. Two of the 3 non responders were obese and only received one infusion of ID. Perhaps a second infusion might have been beneficial. However no relation between weight, response, and ID dosing could be detected. Both patients had normal hemoglobins before the iron infusion but were very symptomatic from their iron deficiency. Both patients experienced a rise in their hemoglobin (1.9 gram% and 1.4 gm%). The third non responder actually had a fall in the hemoglobin from 10.5 to 10.1 gm%. No clear explanation was apparent.
No clear explanation for the female predominance was apparent.
Conclusion:
In 2009 119 million prescriptions for PPI were written in the USA. The gastrointestinal literature suggests that anemia from PPI is uncommon. Very likely IDA due to IM from PPI is much more common than recognized and should be considered for any iron deficient patients without evidence for other causes for IDA. Intravenous iron is highly effective.

Disclosures
No relevant conflicts of interest to declare.