A new meta-analysis on COVID-19 and iron metabolism was released as a preprint* yesterday by researchers from Turkey, Colombia, Hungary, Switzerland, and the Netherlands. Meta-analyses are studies that pool the results of many studies together to look at the net results.
The analysis included 56 studies that together included 14,044 COVID-19 patients. 49 studies reported levels of hemoglobin, an iron-dependent protein that carries oxygen in our blood, and 18 studies reported ferritin, a marker of long-term iron storage. No other markers of iron metabolism were reported.
In 19 studies that reported hemoglobin according to whether patients had moderate or severe cases, severe cases had a mean hemoglobin of 12.96 g/dL, while moderate cases had a mean hemoglobin of 13.38 g/dL. Severe cases had 0.421 g/dL lower hemoglobin.
This was statistically significant at p<0.001. It's a small difference, but the p value means there is only a 0.1% chance we would observe a difference of that strength or greater were it only a result of random chance.
By contrast, hemoglobin levels did not differ between those who died and those who survived.
These hemoglobin levels are slightly anemic or borderline anemic for males, and the patients in these studies were 60% male.
The differences in ferritin were more dramatic. First, the mean ferritin of the whole group was 561 ng/mL. This is very high, considering the typical reference range is 12-300 ng/mL. In four studies that reported ferritin according to disease severity, ferritin levels were 625 ng/mL in those with moderate cases and more than twice as high (1409 ng/mL) in those with severe cases. In another set of four studies that reported ferritin according to mortality, ferritin levels were 546 ng/mL in those that survived and almost triple (1588 ng/mL) in those that died.
This meta-analysis covered studies published up through May 5.
On May 13, researchers from Oxford, UK released a preprint showing the first measurements of serum iron in COVID-19.
They classified 30 ICU patients at the John Radcliffe Hospital in Oxford with COVID-19 into those who had severe or non-severe hypoxemia. Severe hypoxemia was defined as a ratio of arterial oxygen to oxygen breathed into the lungs (the PaO2/FiO2 ratio) of less than 100 mm Hg, and non-severe was defined as 100-300 mm Hg.
Those with severe hypoxemia had a median serum iron of 2.3 umol/L (12.8 mcg/dL), while those with with non-severe hypoxemia had a median almost double that, of 4.3 umol/L (24 mcg/dL). Normal values are 60-170 mcg/dL, so this represents profoundly low serum iron in all subjects, with levels nearly cut in half in severe cases versus non-severe cases.
Transferrin saturation, a marker of short-term iron storage, was 7% in severe cases and 12% in non-severe cases. This difference was not statistically significant (p=0.12). Both of these values are very low. Normal values are 20-50%, and optimal values are 30-40%.
This general picture is consistent with anemia of chronic disease. This is driven by inflammation, mainly mediated by interleukin-6 (IL-6), which prevents iron from being absorbed from food and causes it to be shifted into long-term storage within ferritin. This prevents it from being available to feed pathogenic microbes. According to the iron chapter of Modern Nutrition in Health and Disease, hemoglobin levels will be below 13 g/dL for a male and 12 g/dL for a female, ferritin will be 100 ng/mL or higher, and transferrin saturation will be below 20%.
Normal hemoglobin levels can run as high as 15.5 in women and 17.5 in men, so although the differences in COVID-19 patients are not huge, it doesn't take much to knock someone down to the threshold of anemia of chronic disease.
Inflammation-driven shifting of iron toward ferritin may be robbing red blood cells of the iron needed for hemoglobin. The high metabolic demand of fighting a virus may increase oxygen requirements. Clotting in the small arteries of the lungs may prevent oxygen from reaching the systemic circulation. A borderline or slightly anemic hemoglobin level may aggravate this by reducing the oxygen carrying capacity of the blood.
Since lactoferrin has shown promise specifically in anemia of chronic disease, I'll be jumping into my lactoferrin deep dive tomorrow.
Stay safe and healthy,
Chris
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I am not a medical doctor and this is not medical advice. I have a PhD in Nutritional Sciences and my expertise is in conducting and interpreting research related to my field. Please consult your physician before doing anything for prevention or treatment of COVID-19, and please seek the help of a physician immediately if you believe you may have COVID-19.
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*Footnotes
* The term “preprint” is often used in these updates. Preprints are studies destined for peer-reviewed journals that have yet to be peer-reviewed. Because COVID-19 is such a rapidly evolving disease and peer-review takes so long, most of the information circulating about the disease comes from preprints.