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Heavy Metal: Iron and the Brain

Sometimes the first symptoms of iron deficiency are neurologic.

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Source: Wikimedia commons

Iron deficiency is the most common nutritional problem in the world, affecting at least 2.5 billion people. In developing countries, as many as 40% of young children and 50% of pregnant women are deficient. Iron is a prevalent mineral, making up 5% of the earth’s crust, but a combination of inefficiency in absorption, poor iron in certain staple grain foods, and medical conditions make low iron levels a frequent occurrence among humans. Even in first world countries, iron is the most common nutrient deficiency.

Low iron intake and accelerated iron loss (generally through bleeding or breastfeeding) are the main causes of iron deficiency. Therefore pregnant women, breastfeeding women, women with heavy periods, children and other folks who are picky eaters, vegetarians and vegans, and anyone with digestion issues causing reduced absorption (such as celiac disease or post gastric bypass) or increased bleeding (such as cancer, ulcers, gastritis, or parasites) are at higher risk for iron deficiency. High intake of calcium (for example in kids who drink a ton of milk) can interfere with iron absorption as well, along with commonly used medications such as antacids and proton-pump inhibitors for gastroesophageal reflux disease.

While we are used to thinking of low iron levels as causing anemia due to red blood cells’ requirement for iron as a part of hemoglobin, iron is also desperately needed for the nerves and brain. Severe iron deficiency in young children can cause irreversible damage to cognition and result in lower IQ and developmental delays, particularly during a critical period of human development in utero and up to 16 months of age.

Even in adults the first symptoms of iron deficiency are often neurologic, as those affected will frequently complain of fatigue, brain fog, and also restless legs causing insomnia. Pica, the odd behavioral compulsion to eat nonnutritive foods such as dirt or clay, is extremely common in areas of the world where iron deficiency is prevalent. In the developed world, pica is rare but still occurs in children, pregnant women, and among other groups at higher risk for iron deficiency including those who have had gastric bypass. Non-neurologic symptoms of iron deficiency include pallor, generalized weakness, and higher than usual heart rate along with shortness of breath, particularly with exertion.

Wikimedia commons
Source: Wikimedia commons

Why does iron deficiency cause problems with cognition and neurologic issues like restless legs? The exact mechanisms are mysterious, but without enough iron in the brain and nerves, there are problems with neurotransmitter signaling, the formation of nerve insulation called myelin, and brain energy metabolism. Slowed central neuron processing is considered to be the critical problem of iron deficiency in the brain, which can be a primary cause of all sorts of psychiatric symptoms as well as exacerbating ongoing psychiatric problems.

Sometimes iron deficiency will present as anxiety, depression, irritability, and even poor concentration and general restlessness. For example, iron deficiency has much higher prevalence in children diagnosed with ADHD, and the symptoms can improve with iron supplementation. People with iron deficiency have higher rates of psychiatric disorders (particularly ADHD) and developmental disorders, and there is a growing body of evidence the iron deficiency causes the problems and is not just a chance association.

Iron gets into the brain through the blood brain barrier via transferrin receptors. Iron uptake into the brain is tightly controlled, but it does vary with iron status in the body, so folks with low iron will have less iron going into the brain and those with more iron in the blood will have more iron in the brain. Certain areas of the brain seem to collect iron and have much higher levels than others(1). Again, neurologic symptoms can appear prior to frank iron deficiency anemia, so clinicians cannot rule out iron deficiency from the most commonly ordered simple screening test, a complete blood count. A better general screen is ferritin levels (<15 ng/ml is the diagnostic level for iron deficiency, but levels less than 40 can present with restless legs and other neurologic symptoms). Ferritin on its own can be misleading in populations with high amounts of inflammation (those on dialysis for example), where ferritin levels can be high even if one is iron deficient. A full iron workup includes hemoglobin, MCV, ferritin, total iron binding capacity, serum iron, and transferrin saturation.

Treating iron deficiency is relatively simple via iron supplements or in milder cases encouraging the prudent consumption of foods high in iron. Sometimes people with severe absorption issues will need iron transfusions intravenously. Meat and seafood are the best sources of easily absorbable heme iron, though nonheme iron is found naturally in leafy greens, beans, and nuts.

It is important to be certain of iron deficiency before aggressively treating it with high amounts of iron supplementation. Except for blood loss, the only way to get rid of excess iron is via skin cells flaking off. Therefore populations such as adult men who take lots of iron supplements and those with genetic tendency to absorb more iron from foods are at risk for a condition of severe iron overload known as hemochromatosis. Excess iron is stored in the liver and can lead to scarring of the liver known as cirrhosis, and iron overload can also lead to joint and hormonal problems and a bronze-ish skin color. Symptoms of hemochromatosis include fatigue, joint pain, and low sex drive, and there is a higher risk of diabetes. High serum iron in general is associated with certain health problems such as high blood pressure. Men and women who aren’t iron deficient can consider regular blood donations to prevent accidental iron overload. Iron is one of those Goldilocks minerals that should neither be too high or too low, but rather just right.

More research, particularly into the very common modern conditions of restless legs and ADHD is essential to help us understand the complete relationship between iron and the brain.

(1) the substantia nigra, the globus pallidus, the caudate nucleus, and the putamen.

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