How Iron Overload Became a Metabolic Thing

Healthy Aging

Emergence of a New Threat to Our Metabolism: Iron Overload

A few weeks back, we covered a metabolic storm that has been brewing for decades. In this series, we’re sharing the science behind the earliest igniters of metabolic dysfunction. Just as importantly, we are sharing studies supporting how we can take back control of our long-term health. In the last issue, we shared how aging-related fragile red blood cells can cause whole-body frailty. This week, we talk about how iron overload can impair metabolic function.

Wait. I thought iron deficiency was the big concern, not too much iron.

It ends up, we need to care about both: making sure we have enough iron in our blood but not too much in our tissues. Iron is an essential mineral that helps with oxygen transport, energy production, and muscle function. At high levels, however, iron can cause oxidative stress and lead to a specific type of cell death, called ferroptosis.

Looking specifically at cardiovascular disease (which remains the leading cause of death globally), Ashwara et al. shared the following in their review on the importance of properly balanced iron:

• Iron deficiency can lower energy, exercise capacity, and result in higher cardiovascular-related morbidity.
• Iron overload can cause oxidative stress, arrhythmias, and result in higher risks of cardiomyopathy.

Our “double-edged” relationship with iron translates into a U-shaped curve, where having either too much or too little iron increases one’s risk of poor cardiovascular outcomes.

So, what causes iron deficiency vs. iron overload?

Good question. It is relatively easy to understand how a person can have iron deficiency. You can have: 1) too little iron in your diet, 2) too much iron loss due to blood loss, or 3) too high of a demand (aka pregnancy). In these cases, iron supplementation can be used to get iron levels back up to where they need to be.

In the past, iron overload (which is typically centered in the liver) was pretty much limited to people with an HFE gene abnormality called “hereditary hemochromatosis”.  Even as recently as Pietrangelo’s review paper from 2010, non-hereditary (aka, non-genetic) forms of liver iron overload were characterized as “rare”.

Over the past 20 years, we have seen the emergence and growth of a non-genetic form of liver iron overload that goes something like this:

• In 1999, Mendler et al. identified a distinct form of non-genetic liver iron overload that was consistently linked to insulin resistance, which they called “insulin-resistance hepatic iron overload”.
• During 2005, Trombini & Piperno further linked high ferritin (a biomarker of iron overload) to metabolic syndrome and fatty liver disease.
• By 2008, Riva et al. had published a more formal evaluation of criteria to diagnose this emerging disease, and by doing so, helped to solidify the term “dysmetabolic iron overload syndrome” (aka DIOS).
• Deugnier et al. published a review of DIOS in 2017, including the consistent presence of hyperferritinemia, liver iron overload, and metabolic syndrome that progresses to fatty liver disease, chronic fatigue, and generalized joint pain.
• Then, in 2023, the Nature-published consensus statement from Valenti et al. formally defined how to diagnose “metabolic hyperferritinemia”, which has three progressive grades – the most severe grade (Grade III), being DIOS.
• A year later, Gensluckner et al. showed that a shocking 1 in 10 people in a general population met the formal criteria for metabolic hyperferritinemia.
• Further, Liu et al. published in 2024 that people diagnosed with metabolic hyperferritinemia were associated with more advanced biomarkers of liver disease, kidney disease, and muscle loss (aka sarcopenia). People with Grade II-III metabolic hyperferritinemia also had an increased risk of mortality.

So, we’ve gone from non-genetic iron overload being characterized as “rare” in 2010, to a specific, diagnosable non-gene-based and metabolic dysfunction-associated form of iron overload today that may be present in approximately 1 in 10 people.

Which is where we started with this series (see Science Says! Issue 178). Now that you’re up to speed on metabolic hyperferritinemia, fragile red blood cells, and dysmetabolic iron overload syndrome, we’ll tie everything together for you next week – linking all three to help explain just what’s going on here.

In the meantime, have a wonderful week, everyone!