Catecholamines Increase in the Urine of Non‐Segmental Vitiligo Especially During Its Active Phase

Abstract

Neural factors appear to play a major role in the pathogenesis of vitiligo. To investigate the possible correlation between vitiligo and peripheral monoaminergic system activity, we used high-pressure liquid chromatography and electrochemical detector methods to evaluate the basal urine excretion values of catecholamines [norepinephrine (NE), epinephrine and dopamine (DA)], their relative metabolites [3-methoxy-4-hydroxyphenylglycol (MHPG), normetanephrine (NMN), metanephrine (MN), vanilmandelic acid (VMA) and homovanillic acid], as well as 5-hydroxyindoleacetic acid (5-HIAA), in 35 healthy subjects and in 70 patients, suffering from non-segmental vitiligo at different stages of the disease. Levels of NE, DA, NMN, MN, MHPG, VMA and 5-HIAA were found to be significantly higher in patients than in controls. The patients with progressive vitiligo (n = 56) presented increased urinary excretion values for all parameters (in particular, NE levels) than other patients. Interestingly, in patients at its more recent vitiligo onset (<1 yr), NE values were different to those of subjects affected from 1 to 5 yr and from 6 to 10 yr. This result was confirmed by the significant negative relationship detected between NE excretion values and disease duration. In both vitiligo and control groups, significant correlations were found between monoamines as well as between these monoamines and their metabolites. The increase in catecholamine turnover, mainly occurring at the onset of the disease, is probably due to the stress associated with the appearance of lesions. Moreover, considering that these compounds readily produce toxic free-radicals and that vitiliginous subjects have a defective free radical defence mechanism, they may also contribute to the disappearance of melanocytes in the early phases of vitiligo.

A Critical Appraisal of Vitiligo Etiologic Theories. Is Melanocyte Loss a Melanocytorrhagy?

“…There is, however, no clear link established between local cutaneous cell production of catecholamines and their metabolites and plasma or urine detection, which supports an alternative action of the sympathetic system or of the adrenal glands (45). According to Schallreuter's biochemical theory, excessive de novo synthesis of (6R) 5,6,7,8-tetrahydrobiopterin (6-BH4), the essential co-factor of tyrosine hydroxylase which catalyses the first step of the biosynthesis of catecholamines, is a key factor (49).…”

“…According to Schallreuter's biochemical theory, excessive de novo synthesis of (6R) 5,6,7,8-tetrahydrobiopterin (6-BH4), the essential co-factor of tyrosine hydroxylase which catalyses the first step of the biosynthesis of catecholamines, is a key factor (49). As concerns the relevance to the cause of the disease, the concentration of catecholamines found in vitiligo skin is not considered sufficient to kill melanocytes, and the time course of the production of catecholamines favors a consequence rather than a causal factor (45). However, a link with altered oxidative stress defenses already noted in NSV has been speculated (44), because the generation of an excess of catecholamines produces oxidation products (quinones, semiquinone radicals and hydrogen peroxide-H 2 O 2 -) toxic for melanocytes, providing a basis for a mixed neural-autotoxic (impaired redox status) or biochemical hypothesis (50).…”

“…The level of norepinephrine is elevated in the plasma of NSV vitiligo patients (43). The increase in urinary catecholamines and their metabolites correlates with disease activity and recent onset (44,45). Epinephrine induces white hairs in inbred black rats (46).…”

Beta Adrenergic Receptors in Keratinocytes

“…Since beta2AR-stimulation activates melanogenesis in vitro, it is tempting to propose that blockade of beta2AR on melanocytes in vivo may contribute to the decrease in melanin synthesis seen in vitiliginous skin. Second, patients with vitiligo exhibit increased plasma and urine concentrations of norepinephrine and its degradation products [57][58][59]. One possible source may be from the keratinocytes within the vitiliginous areas, that have increased levels of 6BH4 [58,60] (Figure 2).…”

Autoantibodies Profile in Vitiligo

“…although both genetic [7] and environmental factors are the ones implicated as the major cause [8], however, there are other several factors proposed in the pathogenesis of the disease (Figure 1), these include the following, physical trauma [9,10], psychological stress [11], infections [12], neural factors [11,13,14], biochemical factors [15][16][17], melanocytes growth factors [18], melanocortin hormones [19] and autoimmunity [20].…”