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Restless Leg Syndrome and Iron

Iron supplementation is known to improve the symptoms of restless leg syndrome. Find out the roles iron play in the body, how iron levels in the specific parts of the brain is closely related to dopamine levels and how to take iron to help relieve restless legs.
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What is Iron?

Iron is a trace mineral in living systems. It is especially notable for forming essential protein complexes. Examples of these important biological entities include the oxygen-carrying component of hemoglobin, a related molecule in cellular metabolism called cytochrome and the enzyme, catalase.

In humans, free iron is unavailable because of the biological toxicity of the elemental ions. Instead, iron is bound to different proteins such as transferrin which is responsible for transporting iron absorbed in the duodenum through the blood to the cells.

Inside these cells, iron is bound to ferritin for the same reasons.

Iron is a pretty common mineral available in different plant and animal dietary sources. Common foods with rich stores of iron include red meat, fish, poultry, vegetable, beans and fortified cereals.

Dietary sources of iron are generally classified into two: heme iron and non-heme iron sources.

Heme iron is more easily broken down and absorbed than non-heme iron. It is also the form of dietary iron incorporated into the hemoglobin and other heme proteins.

Meat is a prime source of heme iron while vegetables provide non-heme iron.

Because of its high potential for toxicity, iron uptake, storage, distribution and utilization are strictly regulated in the body. This is especially important because the body has no established mechanism for excreting iron except for the minimal amount lost to the shedding of mucosal and epithelial cells.

Iron deficiency is one of the most common nutritional deficiencies. It occurs for a number of reasons including:

  • Increased demand for iron which is not met by dietary sources
  • Increased loss of iron due to blood loss
  • Reduced dietary intake of iron including malabsorption of the mineral

Iron deficiency is also known as sideropenia or hypoferremia. It is usually common in children and menstruating women.

Symptoms of iron deficiency can occur early before the nutritional imbalance cause more serious problems. Such symptoms include fatigue, dizziness, weakness, pallor, painful wasting away of mucosal surfaces, hair loss, impaired immunity and restless leg syndrome.

What is Restless Leg Syndrome?

Restless leg syndrome is a neurological disorder which is characterized by the urgent, sometimes uncontrollable, need to move to relieve odd sensations in the body.

It is also called Willis-Ekbom disease and it can affect not only the legs but the torso, the arms and even phantom limbs in amputees.

The odd sensation that triggers the irresistible urge to move could be painful or not. It can also be itching, aching, tickling or crawling sensation of the muscle. Movement especially walking can provide temporary relief for such sensations.

Restless leg syndrome is a spectrum disorder. This means that those it affects experience varying degrees of symptoms. Some people have very mild symptoms which may barely meet the criteria for diagnosing the disorders while others clearly experience severe and marked symptoms.

This nature of restless leg syndrome is also the reason for the controversy surrounding the disorder.

Some physician refuse to acknowledge that restless leg syndrome is a separate disorder and not a subset of other neurological diseases. The status of the disorder is not helped by the indiscriminate promotion of dubious claims and off-label uses of some medications by Big Pharma.

Restless leg syndrome affects about 10% of the population. It affects women more than men.

Signs and Symptoms of Restless Leg Syndrome

Restless leg syndrome can either be primary or secondary.

Primary restless leg syndrome is idiopathic. This means that its cause is unknown. This is usually a slow, progressive form of the disorder. It is often first diagnosed before the age of 40 and may remain dormant for a while but it always worsen with age.

Secondary restless leg syndrome is usually diagnosed after the age of 40. It can be caused by an underlying disease or medications. It rarely goes dormant.

There are specific criteria that symptoms of restless leg syndrome must meet to make a diagnosis.

The standard diagnostic criteria set is the one established in 2003 by the National Institutes of Health (NIH). The 4 defining symptoms of restless leg syndrome according to NIH are listed in the table below

NIH Criteria for RLS
  • An urge to move the limbs (especially the leg) with or without experiencing sensations in such limbs
  • Improvement and some relief of symptoms following movement
  • Worsening of symptoms especially with prolong rest
  • Worsening of symptoms in the evening and night. These symptoms are least persistent in the morning

Causes of Restless Leg Syndrome

Underlying Medical Conditions

Certain chronic diseases and at least one nutritional deficiency are known to cause restless leg syndrome. In patients affected by such, treating the underlying medical condition can improve the symptoms of restless leg syndrome.

Chronic diseases related to the syndrome include Parkinson’s disease, diabetes, peripheral neuropathy, kidney disorder, varicose vein, fibromyalgia, rheumatoid arthritis, celiac disease and sleep apnea.

Iron and folate deficiencies are the main nutritional deficiencies related to restless leg syndrome.

The indicator for iron deficiency in patients suffering from restless leg syndrome is low ferritin levels (below 50 micrograms per liter). However, iron deficiency affects only 1 in 5 people living with restless leg syndrome.

In addition, studies show that the substantia nigra (a dark structure located in the midbrain which is known to contribute to reward, addiction and movement) of patients of restless leg syndrome have low levels of iron. Iron is known to cross into the brain where it combines with levodopa to form dopamine and other related neurotransmitters.

Restless leg syndrome is also commonly reported in pregnant women especially during the third trimester. Symptoms of this syndrome usually resolves a month after delivery.

ADHD is also strongly associated with restless leg syndrome. In fact, both disorders share drugs in the same class and these drugs reduce the dopamine levels in the brain.

Chronic alcohol use and sleep deprivation are also associated with this syndrome.

Medications

Some drugs can worsen or even cause secondary restless leg syndrome. Most of such drugs act on the central nervous system and may even cross the blood-brain barrier.

Examples of drugs that may cause this syndrome are antinausea drugs (especially the antidopaminergic ones), antidepressants, antipsychotics, some anticonvulsants and antihistamines in cold medications.

Benzodiazepines sleeping pills may also cause restless leg syndrome when stopped. Similarly, the withdrawal of opioids can also cause this syndrome.

Genetics

Restless leg syndrome also has a strong genetic component. More than 60% of the people living with this syndrome directly inherit it.

The 4 genes known to be associated with restless leg syndrome are MEIS1, BTBD9, MAP2K5 and PTPRD.

In addition, different loci on different chromosomes have been matched to incidence of this syndrome in different cultures.

Studies on Iron and Restless Leg Syndrome

Iron, Restless Leg Syndrome and Pregnancy

Most of the studies done on restless leg syndrome investigate the role of iron deficiency and its relations to the dopaminergic pathway in the development of the disorder. Clearly, low iron levels are commonly seen in restless leg syndrome patients.

A 2001 article published in the Journal of Women’s Health and Gender-Based Medicine examined iron levels in some women before and during their pregnancies.

None of the women had restless leg syndrome before they got pregnant. However, by the third trimester, 23% of them had the syndrome and only 1 of them continued to have the syndrome after giving birth.

The results of the study showed that the women who ended up developing restless leg syndrome during their pregnancies had low serum ferritin levels before conception and even significantly lower folate levels when compared to the women who never developed the syndrome during the study.

In addition, the group of women with the syndrome had delayed onset of sleep and were more depressed.

The study recommended that the recommended normal ranges for serum ferritin and serum folate levels should be reconsidered for pregnant women in order to prevent the occurrence of restless leg syndrome during pregnancy.

Iron, Restless Leg Syndrome and the Brain

In a 2005 paper published in the Journal of Sleep Research, Japanese researchers examined how the level of iron in the central nervous system contributes to restless leg syndrome.

In that study, 10 patients with idiopathic restless leg syndrome and 10 insomnia patients without the syndrome were recruited. The levels of iron, ferritin and transferrin in the serum and cerebrospinal fluid was measured for each of the patient.

While there was only a small difference between the serum values of iron, ferritin and transferring for the two patients groups, there were marked differences for measurements for the cerebrospinal fluid.

The iron and ferritin levels in the cerebrospinal fluids were lower in patients with restless leg syndrome.

However, the transferrin levels in the CSF was higher for patients with the syndrome than those without.

The results showed that the low iron levels in the brains (specifically, in the substantia nigra) of restless leg syndrome patients are most likely caused by inefficient transportation of iron from the serum to the central nervous system.

This means that idiopathic restless leg syndrome is most likely caused dysfunctional transport system for iron and, therefore, low levels of the mineral crossing the blood-brain barrier.

Iron, Restless Leg Syndrome and Dopaminergic Pathway

In a 2009 paper published in Brain: A Journal of Neurology, an in-depth look into the functioning of the brain in restless leg patients was done with autopsy study of the brains of such patients.

The researchers found that the brains of restless leg syndrome patients showed no evidence of damaged cells. Rather, they found that the receptors that help brain cells absorb iron are not well regulated especially in cells that produce dopamine.

This confirms the link between iron and the dopaminergic pathway.

The brain examination also confirmed that iron level in the substantia nigra of the brain was low. In addition, there was only a few receptors for transferrin (the protein that help transport iron into the cells).

Other proteins needed for iron transport and storage were also found in very low amounts.

This study explains why some restless leg syndrome patients have normal serum levels of iron; why iron supplementation works for patients with no iron deficiencies; and why CSF iron levels are a better measure of iron levels for people living with this syndrome.

Therefore, restless leg syndrome is not strictly caused by iron deficiency even though iron supplementation improves its symptoms.

Rather, the syndrome is caused by problems with iron transportation and delivery to the brain.

This iron insufficiency leads to reduced production of dopamine. Low levels of dopamine means that there is lesser control of motor activity which then produces the restless movement seen with the syndrome.

How to Take Iron for Restless Leg Syndrome

Iron supplementation works best for restless leg syndrome patients with iron deficiency.

There are different forms of iron supplements available each with its own absorption profile. Iron supplements should be taken between meals for maximal absorption. However, it can also be taken with food especially when it causes gastrointestinal disturbance.

65 mg of iron (325 mg for ferrous sulfate; the equivalent will depend on the actual iron supplement taken) taken 3 times daily is the recommended dosage for treating this syndrome. You should also drink a lot of water after taking iron pills.

Usually, iron is not the only nutritional supplement that should be used in the treatment of restless leg syndrome. Since folate levels are also low in many patients with this syndrome, folic acid supplement may also be combined.

Therefore, a good approach is to use a combination nutritional supplement containing minerals, vitamins, amino acids and herbal extracts proven to improve the symptoms of restless leg syndrome.

A good example of such nutritional supplement is Sedorum.

Sources


http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001810/

http://www.webmd.com/sleep-disorders/guide/restless-legs-syndrome-rls

http://www.rls.org/

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