Effects of suboptimal oxygen and iron on learning and behavior

Oxygen is critical for brain function and iron is necessary to get it there. It’s worth re-visiting a study published six years ago in the journal Pediatrics that documents the profound effects of even intermittent hypoxia.

“A review of the evidence concerning the effect of chronic or intermittent hypoxia on cognition in childhood was performed by using both a systematic review of the literature and critical appraisal criteria of causality.”

The authors applied rigorous appraisal criteria to massive amounts of data narrowed down to 55 studies to resolve their findings:

Adverse effects were noted at every level of arterial oxygen saturation and for exposure at every age level except for premature newborns.”

Their conclusions are emphatic:

Adverse impacts of chronic or intermittent hypoxia on development, behavior, and academic achievement have been reported in many well-designed and controlled studies in children with CHD [congenital heart disease] and SDB [sleep-disordered breathing] as well as in a variety of experimental studies in adults…Because adverse effects have been noted at even mild levels of oxygen desaturation, future research should include precisely defined data on exposure to all levels of desaturation.”

Ferritin is the ‘storage’ form of iron in the bloodstream and one of the more reliable indicators of iron availability and utilization. Suboptimal ferritin can affect learning and behavior in two ways: by diminishing the oxygen-carrying capacity of the blood due to less hemoglobin, and by limiting the production of key neurotransmitters. The authors of a paper published in the journal Child Psychiatry & Human Development state:

“Our aim was to investigate the relation between behavioral symptoms and hematological variables which are related with iron deficiency and anemia, ferritin, hemoglobin, mean corpuscular volume (MCV), and reticulosite distribution width (RDW) in children and adolescents with pure Attention Deficit Hyperactivity Disorder (ADHD) or ADHD comorbid with other psychiatric disorders.”

The authors correlated results from the Conners Parent (CPRS) and Teacher Rating Scales (CTRS) the metrics for anemia and iron insufficiency. Their data showed that when ADHD was present with other problems (comorbidities) the association was pronounced:

“Comorbid ADHD subjects had lower mean hemoglogin and MCV. In the ADHD group in general, CPRS and CTRS Total scores were significantly negatively correlated with ferritin level. When only pure ADHD subjects were taken into account, the correlations did not reach statistical signifance. Overall, these results suggested that lower ferritin level was associated with higher behavioral problems reported by both parents and teachers. Presence of comorbid conditions might increase the effect of lower iron stores on behavioral measures.”

An interesting study published in the journal Sleep Medicine investigates the association of Restless Legs Syndrome (RLS) and iron deficiency on ADHD. The authors state:

“Increasing evidence suggests a significant comorbidity between attention-deficit/hyperactivity disorder (ADHD) and restless legs syndrome (RLS). Iron deficiency may underlie common pathophysiological mechanisms in subjects with ADHD plus RLS (ADHD+RLS). “

The data provided further evidence for the impact of iron deficiency on ADHD:

“The mean serum ferritin levels were significantly lower in children with ADHD than in the control group. There was a trend for lower ferritin levels in ADHD+RLS subjects versus ADHD. Both a positive family history of RLS and previous iron supplementation in infancy were associated with more severe ADHD scores.”

The authors offer useful advice to clinicians and parents in their conclusion:

“Children with ADHD and a positive family history of RLS appear to represent a subgroup particularly at risk for severe ADHD symptoms. Iron deficiency may contribute to the severity of symptoms. We suggest that clinicians consider assessing children with ADHD for RLS, a family history of RLS, and iron deficiency.

Additional research published in Pediatrics documents further the adverse effect of intermittent hypoxia and snoring on childrens’ behavior. The authors’ objective:

Sleep-disordered breathing is associated with impaired behavior and poor academic performance in children. We aimed to determine the extent of behavioral problems in snoring children, clarify the role of intermittent hypoxia, and test the reversibility of impaired behavior and poor academic performance.”

They included 1144 children in their study, correlating snoring, oxygen saturation with pulse oximetry, and impaired behavior using parental questionnaires and academic performance. The evidence was striking:

HS [habitual snoring] was significantly associated with hyperactive and inattentive behavior , daytime tiredness , and sleepiness. These associations were independent of intermittent hypoxia. HS was also significantly associated with bad conduct, emotional symptoms , and peer problems.

Moreover, although academic success did not make a big change when snoring ceased, hyperactive and inattentive behavior improved significantly. The authors conclude:

“We suggest that impaired behavior is a key feature of HS independent of intermittent hypoxia and improves when HS ceases.”

We can add to the above evidence another study published in the Archives of Pediatrics & Adolescent Medicine that also investigates the link between iron deficiency and ADHD. In addition to lower hemoglobin…

Iron deficiency causes abnormal dopaminergic neurotransmission and may contribute to the physiopathology of attention-deficit/hyperactivity disorder (ADHD).”

Again we see serum ferritin levels correlating with the Conners’ Parent Rating Scale scores measuring severity of ADHD symptoms:

“The mean serum ferritin levels were lower in the children with ADHD…In addition, low serum ferritin levels were correlated with more severe general ADHD symptoms measured with Conners’ Parent Rating Scale…These results suggest that low iron stores contribute to ADHD and that ADHD children may benefit from iron supplementation.”

Fibromyalgia, iron and neurotransmitters

European Journal of Clinical NutritionMost readers are aware that low iron reduces oxygen delivery to tissues, and this degrades the ability of every cell to produce energy for function. Naturally this can contribute to chronic pain of various kinds. This valuable paper published in the European Journal of Clinical Nutrition about fibromyalgia brings up another important point: low neurotransitters (dopamine, norepinephrine, serotonin) are a contributing cause of the pain and dysfunction of fibromyalgia, and adequate iron is necessary for their production. The authors begin by observing:

Iron is essential for a number of enzymes involved in neurotransmitter synthesis. Analysis of cerebrospinal fluid in fibromyalgia syndrome (FMS) has shown a reduction in the concentration of biogenic amine metabolites, including dopamine, norepinephrine and serotonin. This study aimed to investigate the association of ferritin with FMS.”

To investigate this association serum ferritin, vitamin B12 and folic acid were measured in 46 patients with primary FMS and 46 healthy controls. Their data paints a very interesting picture:

“Binary multiple logistic regression analysis…showed that having a serum ferritin level <50 ng/ml caused a 6.5-fold increased risk for FMS.”

Here’s what the authors concluded from their findings:

“Our study implicates a possible association between FM and decreased ferritin level, even for ferritin in normal [see note below] ranges. We suggest that iron as a cofactor in serotonin and dopamine production may have a role in the etiology of FMS.”

Important: there is earlier research that validates 50 ng/ml as the correct low point for serum ferritin, but many labs have not caught up and still have a report with a reference range for ferritin that is too low. This is a key point in clinical practice.

Fibromyalgia, iron and neurotransmitters

European Journal of Clinical Nutrition 0310You might think that functionally low iron would contribute to the pain and fatigue of fibromyalgia through its effect on the oxygen carrying capacity of the blood, which would not be incorrect. But as this study just published in the European Journal of Clinical Nutrition reveals, there is another very important effect of suboptimal iron levels.

“Iron is essential for a number of enzymes involved in neurotransmitter synthesis. Analysis of cerebrospinal fluid in fibromyalgia syndrome (FMS) has shown a reduction in the concentration of biogenic amine metabolites, including dopamine, norepinephrine and serotonin. This study aimed to investigate the association of ferritin with FMS.”

Ferritin, a protein that stores iron, is the most accurate single quantifier for iron stores in the body. Adequate iron is mandatory for the production of neurotransmitters including dopamine and serotonin (one of the reasons why depression occur around the time of menses). What did their data show?

“…having a serum ferritin level <50 ng/ml caused a 6.5-fold increased risk for FMS.”

Doctors (and everyone), notice the serum ferritin level. Many practitioners are not aware of other research showing that the common laboratory reference ranges for ferritin are too low and that 50 ng/ml should be the cut-off point. Additionally, there are a number of mechanisms by which suboptimal dopamine and/or serotonin production can affect the experience of pain and fatigue with FMS.

The authors’ conclusion is consonant with the existing evidence:

“Our study implicates a possible association between FM and decreased ferritin level, even for ferritin in “normal” ranges [quotation marks added]. We suggest that iron as a cofactor in serotonin and dopamine production may have a role in the etiology of FMS.”

If there is a question about iron, have your serum ferritin checked (at least) and make sure that it is not lower than 50 ng/ml.