RLS: Imbalance between thyroid and dopamine Pereira Jr. JC et al. disorder that can be seen in approximately 1% to 15% of normal individuals; 5% to 10% of adults in Northern European population–based studies report RLS symptoms.1,2 The prevalence of RLS is increased with pregnancy, uremia, anemia, and rheumatoid arthritis; it is more common in women than men and its onset can occur at any age.3 It is now understood that considerably severe RLS can occur in up to 0.5% of children and 1% of adolescents.4 Significant variability in the severity of RLS is not uncommon. In the most severe cases, RLS may seriously impact a patient’s quality of life.1-7 The currently accepted definition of adult RLS from the “International Restless Syndrome Study Group (IRLSSG)” and the “International Classification of Sleep Disorders, second edition (ICSD-2)”, are described below. All four features are necessary to make the diagnosis in adults and children.1,2,7 1) An urge to move the legs is usually accompanied or caused by uncomfortable and unpleasant sensations in the legs. 2) The urge to move or unpleasant sensations begin or worsen during periods of rest or inactivity, such as lying or sitting. 3) The urge to move or unpleasant sensations are partially or totally relieved by movements such as walking or stretching, as long as the activity continues. 4) The urge to move or unpleasant sensations are worse in the evening or night than during the day or only occur in the evening or night. The supportive clinical features of RLS include a positive family history of RLS, periodic limb movements during sleep, and periodic limb movements during wakefulness. An additional supportive clinical feature is the “improvement of RLS symptoms with DA therapy”.1,2,7 IRON LEVELS, TYROSINE HYDROXYLASE, CYTHOCROME P450, DA AND TH Among the associated clinical features of RLS, as stated by the IRLSSG, is a serum ferritin level <50 gµ/L. 7 Ferritin, an iron-binding protein is, at low levels, one of the most sensitive indicators of iron deficiency. Iron is a cofactor of tyrosine hydroxylase, a limiting enzyme in the synthesis of DA. Local iron deficiency in the substantia nigra could impair dopaminergic receptors or transporters. At the present time, there is robust evidence that low iron levels are one of the causative factors of RLS or of increasing its severity.8-10 Diminished DA function has a role in RLS symptoms, as can be inferred from the fact that DA agonists are beneficial to RLS patients, whereas antagonists are detrimental, and low iron levels are a putative cause of decreased DA function.8 548 CLINICS 2010;65(5):547-54 The cytochrome P450 (CYP450) superfamily is another enzymatic complex that is down-regulated in response to iron scarcity.11 CYP450 is constituted by heme proteins and, thus, contains iron.12 In TH metabolism, the CYP450 complex is very important in the degradation of TH through what is called the “Phase 1 elimination of a drug”.13 Drugs that inhibit CYP450 activity down-regulate the degradation of substances, such as TH, that are substrates of CYP450. The opposite occurs with drugs that induce CYP450 activity.13 The evidence described above allows us to infer that not only is iron deficiency a limiting condition for tyrosine hydroxylase activity, which is detrimental to RLS patients, but it also reduces CYP450 activity. It is important to also consider data previously published in the medical literature demonstrating that DA modulates TH, that is, DA depresses the TH axis.14-16 Because the DA system enhances CYP450 activity and TH is a substrate for CYP450 enzymatic activity, it is possible to infer that one way that the DA system can modulate TH is via CYP450: the activation of CYP450 down-regulates TH.17 Furthermore, DA and DA agonists inhibit TSH secretion.16 CYP450 isoforms are expressed in the liver and other peripheral organs, and also in glial cells and neurons in the brain18 (Figure 1). Figure 1 - A diagram showing the abnormal directions that DA and THs take under conditions of iron scarcity, and the resulting imbalance between DA and THs. Dopamine (DA). Thyroid Hormones (THs). DAILY TSH PROFILE AND CIRCADIAN ASPECTS OF RLS SYMPTOMS In the field of basic sleep science, an analysis of the daily TSH profile and its correlation with sleep phase is of great relevance. Also relevant is the comparison of the daily TSH profile and the propensity to sleep during times of the day that are not synchronized with sleep phase timing. The normal daily pattern of TSH secretion shows a circadian variation; circulating TSH concentrations are low and relatively stable during the daytime. TSH levels then begin an acrophase in the early evening, with a steep increase before sleep onset, and peak at around the beginning of the Copyright © 2010 CLINICS