The hidden dangers of higher iron levels

Naturally higher iron levels may reduce the risks of high cholesterol levels and atherosclerosis, but may increase the risks of blood clots—which can trigger stroke and deep vein thrombosis—and bacterial skin infections, according to the results of two recent sister studies published in the Journal of the American Heart Association and PLOS Medicine.

A well-documented chronic health problem, iron deficiency affects about 1.2 billion people worldwide, and is responsible for approximately 35 million years lived with disability annually. Iron deficiency can lead to anemia and other serious health problems if left untreated. On the other end of the spectrum is iron overload, where the body stores too much iron. However, the etiologies and impacts of excess iron levels have not been as extensively studied. Iron overload is most commonly attributed to iatrogenic iron overload related to blood transfusions, as well as hemochromatosis—an inherited condition in which the body absorbs too much iron, which can end up clogging organs like the skin, heart, liver, and pancreas.

“Iron is a crucial mineral in the body, and is essential for carrying oxygen around the body. However, getting the right amount of iron in the body is a fine balance—too little can lead to anemia, but too much can lead to a range of problems including liver damage,” explained the lead author of both studies, Dipender Gill, MD, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.

Reduced risk of high cholesterol

Approximately 25% to 65% of differences between individuals in iron levels are attributed to genetic factors, noted joint first author of the PLOS Medicine paper Beben Benyamin, PhD, Australian Centre for Precision Health, School of Health Sciences, University of South Australia, Adelaide, Australia.

To further explore the broad clinical impact of variations in iron levels—particularly naturally higher levels—on a range of medical outcomes, Drs. Gill and Benyamin and colleagues performed a Mendelian randomization study.

Specifically, they used genome-wide association study summary data collected from nearly 49,000 European individuals across 19 cohorts in the Genetics of Iron Status Consortium to identify 3 genetic variants—rs1800562 and rs1799945 in the hemochromatosis gene, and rs855791 in the transmembrane protease serine 6 gene—that have been linked to increased serum iron, ferritin, and transferrin concentrations as well as decreased transferrin levels, thus serving as instruments for systemic iron status.

They then performed a phenome-wide association study of these instruments on over 424,400 European adults in the UK Biobank (40–69 years of age when recruited from 2006 to 2010), with their genetic data linked to Hospital Episode Statistics from 1995 to 2016. 

“We used a statistical method, called Mendelian randomization that employs genetic data to better estimate the causal effect of iron status on 900 diseases and conditions,” Dr. Benyamin explained. “Through this, we found a link between excess iron and a reduced risk of high cholesterol.”

“This could be significant given that raised cholesterol is a major factor in cardiovascular disease and stroke, causing around 2.6 million deaths each year according to the World Health Organization,” he added.

Increased risk of skin infections

However, Drs. Gill and Benyamin and fellow researchers also discovered that high iron levels could increase the risk of bacterial skin infections, including cellulitis and abscesses. Of note, about 21 million people each year develop cellulitis, which results in over 17,000 deaths globally, positioning it as a global health priority.

Previous researchers have indicated that iron may play a role in bacterial replication and virulence, which may be associated with the increased risk of skin infections, according to Dr. Gill.

Increased risk of stroke

In a related Wellcome Trust-funded investigation published in the Journal of the American Heart Association, Dr. Gill and a team of international scientists performed another Mendelian randomization study, this time to evaluate the effect of genetically determined iron status on carotid intima-media thickness (cIMT), carotid plaque, and venous thromboembolism (VTE).

To proxy iron status, they obtained single-nucleotide polymorphisms from a genome-wide association study meta-analysis performed by the Genetics of Iron Status consortium that combined data from 48,792 European individuals. As in the Biobank study, serum iron, ferritin, and transferrin concentrations were used as instruments for systemic iron status.

Data from 12 studies representing over 7,500 patients with VTE and over 52,600 controls were used for VTE estimates. Furthermore, data from 31 studies for cIMT and 17 studies for carotid plaque trait— incorporating over 71,100 and 48,400 participants, respectively—were used for genetic association estimates for cIMT and carotid plaque.

Dr. Gill and colleagues found that higher genetically determined iron status was linked to an increased risk of VTE, noting the following OR per SD increase in biomarker levels: serum iron, 1.37 (95% CI: 1.14-1.66); transferrin saturation, 1.25 (95% CI: 1.09-1.43); ferritin, 1.92 (95% CI: 1.28-2.88); and serum transferrin, 0.76 (95% CI: 0.63-0.92).

In contrast, they found that increased levels of iron were also linked to a lower risk of carotid plaque. ORs were 0.85 (95% CI: 0.73- 0.99) for serum iron and 0.89 (95% CI: 0.80-1.00) for transferrin saturation; the investigators observed concordant trends for serum transferrin and ferritin that did not reach statistical significance. Moreover, the researchers did not identify any Mendelian randomization evidence of an effect of iron status on cIMT.

“These studies reveal new avenues of research, and present many questions. We are still unclear on how iron affects cholesterol levels, narrows arteries, and forms blood clots, but we have ideas. One possibility is that the lower cholesterol levels may be linked to the reduced risk of arteries becoming furred [with atherosclerotic plaques]. Furthermore, higher iron levels may cause blood clots to arise when flow is reduced, possibly explaining the increased chance of clots,” Dr. Gill stated.

Of note, these studies only assessed naturally occurring iron levels in the body related to genetic variation between individuals—and did not evaluate the effect of taking iron supplements. Thus, individuals should consult their doctors before starting or stopping iron supplements.