Caution urged as low iron linked to PPI use

There appears to be a dose-response relationship between iron levels and PPI use, but how strong is the evidence?

Patients taking proton pump inhibitors could be at an increased risk of iron deficiency, with the risk being greater with higher doses and a longer duration of use, Australian research indicates.

Both PPI use and iron deficiency are common among patients in primary care, but it has been unclear whether there was a relationship between the two, and to what extent.

“Hypochlorhydric states have long been known as an important cause of iron deficiency,” Dr An Tran-Duy and colleagues wrote in their article, adding that it was not known if this also occurred when PPIs caused the hypochlorhydria.

Now, a study of 55,000 patients in a UK primary care database has shown a link between chronic PPI use and iron deficiency, and that there appears to be a dose-response relationship.

Researchers at the University of Melbourne and in the Netherlands analysed the dataset, looking at the PPI use among those with a first-time diagnosis of iron deficiency between 2005 and 2016. They compared those who were taking PPIs continually for at least a year before diagnosis, those who took them intermittently and those who had received no PPI prescription before being diagnosed.

Anyone taking histamine type 2 receptor antagonists, sodium bicarbonate- or calcium carbonate-based antacids was excluded from the study because the former also suppresses gastric acid and those specific antacids are known to potentially interfere with iron absorption if taken long-term.

When controlling for age, sex and general practice, the investigators found that those taking PPIs continuously for more than a year were more likely to become iron deficient compared with those taking the medication for less than a year.

Similarly, patients taking a standard dose of a PPI daily were at greater risk of developing iron deficiency than patients whose PPI use averaged less than this.

“Our findings suggest that physicians prescribing PPIs for a duration of more than a year should be aware of the risk for developing iron deficiency and consider routine monitoring of haemoglobin levels in patients with suspected symptoms,” the authors wrote.

“Furthermore, physicians should also check if patients with iron deficiency are receiving PPIs so that appropriate measures to minimise the consequences of iron deficiency can be determined.

“When it comes to the prescription of these drugs, physicians should weigh their benefits against their harms and try to reduce the dose and length of use as much as possible when appropriate,” study author and senior research fellow Dr Tran-Duy told The Medical Republic.

But gastroenterologist and clinical epidemiologist Dr Suzanne Mahady pointed to some important limitations in the research, such as the failure to adjust for aspirin and anti-inflammatory use, which were likely to be common and important confounders in this study population.

Case control studies such as these were some of the weakest evidence in making the case for an association being causal rather than simply correlational, and the higher proportion of patients with comorbidities such as inflammatory bowel disease in the iron deficient group might have played a bigger role than PPI use, the senior lecturer at Monash University said.

“Their conclusions are too enthusiastic based on the level of evidence they have,” she said.

Dr Tran-Duy told The Medical Republic that in Australia  more than 60% of people taking PPIs had no appropriate indication.

“A lot of money has been spent on unnecessary therapy with these drugs which has a negative impact not only on patient health, but also on healthcare budget planning,” he said.

J Intern Med 2018; online