Chris MasterJohn has just sent out an email on ferritin
This is educational in nature and not medical or dietetic advice. See terms for additional and more complete disclaimers.
Did you know that ferritin, used to measure iron in your blood, contains almost no iron? If not, buckle up, because you’re understanding of ferritin is in for a ride.
Too much iron will make you age faster, wrinkle your skin, give you diabetes, and worsen your risk of heart disease.
Too little iron will crash your brain, leave you fatigued, mess with your hormones, and make it difficult to exercise.
We need iron to be juuuuuust right.
Unfortunately, both the signs and symptoms as well as dietary intake on paper can be deeply misleading. Our iron status has at least as much to do with how our genetics are shaping our iron absorption than how much we are eating. And some of the signs of deficiency and excess are the same.
That is why we need the right testing.
Unfortunately, many doctors simply run ferritin to look at iron status and nothing more.
It is very well established why this is a bad idea. Anemia of inflammation, also called anemia of chronic disease, results from ferritin trapping iron and making it unusable. It can cause functional iron deficiency that coexists with high ferritin. Less well known is that oxidative stress can do the same.
That is why the Comprehensive Nutritional Screening and Testing Nutritional Status: The Ultimate Cheat Sheet use ferritin alongside a full iron panel and a complete blood count to develop a much fuller understanding of what is happening to iron within your body.
However, what is not well understood at all is that literally no one, not me, not you, not your doctor, and not the global leaders in ferritin research, understand how ferritin gets into your blood or what on earth it is doing there.
It certainly isn’t there to carry iron around to your body.
Now, we do know that inside the cell ferritin is the primary protein that binds iron as a dynamic, short-term reserve. It is a large, globular structure with channels big enough to allow iron through, but not most molecules, and with redox-reactive transfer mechanisms that allows transfer of electrons to and away from the iron within it so that it can be oxidized for storage or reduced for release.
We also know that ferritin contains light chains and heavy chains, and the heavy chains have the ability to oxidize iron so that it can be bound. 24 units of these chains combine together to make one ferritin globule, and each globule can store thousands of iron atoms. The proportion of heavy and light chains differ by tissue. Since the heavy subunit provides dynamic redox activity, it is associated with tissues that do not engage in long-term iron storage, such as heart, kidney, and bone marrow. By contrast, the liver and spleen, which engage in long-term iron storage, have a higher proportion of light subunits.
But consider these difficulties that we have in understanding its role in blood:
- Unlike intracellular ferritin, which is an iron storage protein, the ferritin in serum contains almost no iron .
- Serum ferritin contains exactly 24 subunits, just like intracellular ferritin, suggesting it is not broken or partially degraded. However, it contains almost no heavy subunits, and the light subunits are a unique, truncated form.
- Experiments in mice suggest that the liver does not contribute to serum ferritin, and that macrophages do, but that there are numerous other tissues that must make a contribution and we do not know what they are.
- However, all cells that have been established to secrete ferritin secrete a ferritin that looks like intracellular ferritin, not a ferritin that looks like serum ferritin. Thus, either an unidentified cell type is responsible for secreting serum ferritin in vivo, or most secreted ferritin is quickly taken up by neighboring cells, leaving a minority “serum type” to reside in the serum.
The best review of this topic was published 13 years ago. In preparing this article I talked to a researcher who told me that it is essentially up to date in the sense that we still don’t know the answers to any of the mysteries bulleted above, although the next 13 years were said to look very promising.
Consider this: how can we go about measuring ferritin alone as a marker of iron status and making major conclusions from it, when we don’t even understand why it’s in the blood or what it’s purpose is?
In the 1970s and early 1980s, it was established that serum ferritin correlates with body stores.
It is one thing to correlate, it is quite another to be a very sensitive and specific marker.
In 1982, it was shown that serum ferritin has a 59% correlation with iron stores as estimated by bone marrow iron content. Note that the x axis below is linear and the y axis is logarithmic, so the vertical spread looks much more condensed than it really is.
On the one hand, they correlate. On the other, the spread is so large that we cannot conclude much beyond the fact that a serum ferritin between 50 and 200 is consistent with normal bone marrow iron stores.
Numerous other studies were done in the 1970s and 1980s showing that ferritin was elevated in hemochromatosis, very low in iron deficiency anemia, and also elevated in conditions where iron was not in excess, such as inflammatory disorders. There were also studies showing that ferritin and bone marrow iron both correlate with the decrease in iron absorption from food and the increase in urinary iron excretion that occurs with better iron status.
One thing that is clear is that when the liver perceives the body has greater iron status and releases the hormone hepcidin as negative feedback, serum ferritin does go up. We know this because everything that would raise hepcidin — for example iron, or inflammation — raises serum ferritin.
Yet we also know from animal experiments that the liver is not what releases the ferritin, and we don’t know where it comes from or why it’s there.
Is the 41% of the variation in serum ferritin that is not explained by iron status all explained by inflammation and oxidative stress?
Maybe. But without knowing the purpose of serum ferritin we cannot address this question from first principles and without having studies of bone marrow iron content that feed inflammatory and oxidative stress markers into a complex multivariable function we cannot address the math.
So we simply do not know.
My guess is that the drop in ferritin after blood donation is often not entirely explained by a drop in iron status. If you decrease the excess free iron, you will decrease oxidative stress, and that will cause a bigger drop in ferritin than would have occurred from the drop in iron status alone.
On the other hand, this does not mean that we should just throw out ferritin measurements. Indeed, if your ferritin is 10 ng/mL, you have a problem. If it’s 1000 ng/mL, you have a problem. If it’s 500 ng/mL, you have one of several possible problems.
At the extremes, it becomes rather sensitive and semi-specific for major problems.
In the middle, though, it’s hard to say what it means. Your ferritin went from 100 to 60 ng/mL?
Cool. But why?
Again this is why the Comprehensive Nutritional Screening and Testing Nutritional Status: The Ultimate Cheat Sheet use ferritin alongside a full iron panel and a complete blood count to develop a much fuller understanding of what is happening to iron within your body.
Ferritin is useful to measure when you acknowledge its limitations, and one of those limitations is that we still don’t understand how it gets into serum and why.
