aBioinformatics and Medical Informatics Research Center, San Diego State University, 5500 Campanile Dr, San Diego, 92182, USAbDepartment of Chemistry, University of Swabi, Anbar, 23561, K.P.K, PakistancDepartment of Pharmacy, Abdul Wali Khan University, Mardan, 23200, PakistandCentre for Life Sciences, Central University of Jharkhand, Brambe, Ranchi, 835205, Jharkhand, IndiaeDepartment of Marine Chemistry and Natural Products, Ocean College, Zhejiang University, Hangzhou, 310058, PR China
A R T I C L E I N F O
Article history:Received 10 April 2017Received in revised form 12 May 2017Accepted 22 May 2017
Vitiligo is an idiopathic systemic autoimmune disease affecting skin, hair and oral mucosa. This geneticyet acquired disease characterized by melanin loss is a cause of morbidity across all races. Though thyroiddisturbance has been recognized as a key trigger of this pathology, an array of other factors plays criticalrole in its manifestation. Multiple hormones (corticotropin-releasing hormone, adrenocorticotropichormone, a-melanocyte-stimulating hormone, melatonin, calcitriol, testosterone, estrogen), genes(Human leukocyte antigen (HLA), Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), Forkhead boxD3 (FOXD3), Cluster of differentiation 117 (CD117), Estrogen receptor (ESR) 1, Cyclooxygenase-2 (COX2),Vitiligo-associated protein 1 (VIT1)), and lifestyle choices (stress, diet, cosmetic products, andmedications) have been suspected as drivers of this disorder. The pathological mechanisms have beenunderstood in recent times, with the aid of genomic studies; however a universally-effective therapy isyet to be achieved. This review discusses these under-investigated facets of vitiligo onset andprogression; hence, it is expected to enrich vitiligo research.
Vitiligo, a systemic autoimmune disease affecting skin is acomparatively lesser-investigated pathology [1]. This disease,characterized by depigmentation or melanin loss, is mostly non-fatal, but it has its harmful consequences [2]. Depleted melano-cytes (melanin cells) expose skin epidermis to UV light, whichincreases the chances of skin irritation and cancer. Also, the patchy
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appearance leads to psychological disturbance to the sufferer [3]. Itleads to emotional distress, low self-esteem [4] and affects sexuallife of the patients [5]. Often the affected persons, especially thechildren, get bullied and stigmatized [6]. This disease, also knownas leukoderma is pervasive across all races, though instances arehigher in some [7]. For example, the activity of tyrosinase, theenzyme responsible for catalyzing melanin synthesis, is higher inBlack skin melanocytes [8], than that of Caucasian skinmelanocytes.
This disease can appear at any age, though evidences suggestthe higher chances of occurring before the age of 20 [9,10].Symptoms of the onset include itching, and the development ofwhitish maculae on the skin [11]. The manifestation of the diseaseis variable such as generalized or segmental, where the former issymmetrical [12], and the latter affects only one lateral half of thebody [13]. Depending on the distribution of white patches, thedisease has been classified as vitiligo focalis (depigmentation inone area), vitiligo segmentalis (depigmentation in quasi-dermato-mal pattern), vitiligo acrofacialis (depigmentation in face anddistal extremities), vitiligo vulgaris (depigmentation all over thebody), or vitiligo universalis (depigmentation of entire body) [14–17]. Vitiligo often co-exists with other autoimmune disorders, suchas Sutton or halo nevus (mole surrounded by depigmented halo),and malignant melanoma [18,19]. At present, one percent (0.5–2%)of the total world population suffers or is prone to vitiligo [20].
Several genetic factors of vitiligo have been identified throughgene expression, allelic association and genome-wide linkagestudies [21]. The candidate genes span multiple chromosomes.Such genes include HLA, AIRE, VIT1, CAT, FOXD3, ESR1, COMT,PTPN22, NALP1, PDGFRA, MYG1, MITF, CD117, XBP1, FAS, COX2,EDN1 and ACE [22]. These genes are harbored in chromosomes 1(COX2, FOXD3); 2 (VIT1/FBXO11); 4; 6 (HLA); 7; 8; 9; 14; 17(NLRP1); 19; 21 (AIRE); and 22 (COMT) [22–26]. These findingsjustify the polygenic, familial clustering (non-Mendelian pattern)nature of vitiligo [22]. Genotyping studies have revealed severalsingle-nucleotide polymorphisms (SNP) in the genes mentionedabove, which might be linked to vitiligo.
Vitiligo is often associated with pernicious anemia, psoriasis,Addison's disease, rheumatoid arthritis, adult-onset insulin-dependent diabetes mellitus, systemic lupus erythematosus(SLE), inflammatory bowel disease (IBD), and infertility, thusforming a cluster of diseases with common genetic basis [27].Sporadic vitiligo is associated with above-mentioned autoimmunepathologies and often manifest in blood relatives [27–29]. Itsshared genetic basis with another severe autoimmune disease SLEhas come forth [30]. Based on the evidences, the link betweenvitiligo and celiac diseases have been proposed [31].
Vitiligo has a complex etiology and unpredictable progressionand cessation pattern, for it responds to a number of endocrinesignals. Though several genes are responsible for this disease, theirtriggers can be variable. Psychological stressor (emotional strain) isone factor [32]. Stress products such as reactive oxygen species(ROS) can be produced by exogenous and endogenous stimuli [33].
There is no assured therapy available for vitiligo. However,some medications can restore the pigments. For immunosuppres-sion, topical corticosteroids such as glucocorticosteroid (mome-tasone furoate), prednisolone and hydrocortisone areadministered [34]. But, the steroid treatment can lead to sideeffects such as nausea, dizziness, erythema (redness or rash),itching, burning, skin thinning, skin atrophy, and telangiectasia(dilated capillaries visible through skin) [35–37]. Phototherapyincludes light exposure and narrowband UV B laser radiation [38].Calcipotriol (derivative of hormone calcitriol, a form of vitamin D)and psoralen (furocoumarins) with UVA light are often prescribedas non-surgical re-pigmentation therapy in vitiligo patients [18].Calcineurin, a calcium-dependent serine/threonine protein
phosphatase expressed by the neurons, cardiac cells, muscle cells,and lymphocytes has been discovered to play role in vitiligopathogenesis [39]. To block its activity, calcineurin inhibitor (usedfor atopic dermatitis and lymphoma therapy) is used. Genericdrugs of these inhibitors, such as tacrolimus and pimecrolimus,have been successfully used to treat vitiligo [39]. However, theinhibitor has been associated with side effects like posteriorreversible encephalopathy syndrome (PRES), a cluster of healthconditions including headache, seizures, lack of visual co-ordina-tion, and altered consciousness [40,41]. For temporary camouflage,self-tanning dyes are administered. Potassium permanganate,indigo-carmine, Bismarck brown, and henna (Lawsonia sp.) pasteare some of preferred tanning agents [42]. Dihydroxyacetone(DHS), a glycerone-based camouflage creams are popular. Thistriose sugar reacts with amino acid of the skin corneum by Maillardreaction, forming a brown-colored complex [43,44]. However,long-term usage of DHS puts additional stress on skin and causestoxicity Petersen et al. [44]. Cosmetic tattoos are another option,especially for masking depigmentation around the lips [45,46].Surgical interventions through laser therapy and skin grafting areperformed in some cases [47]. Antibiotic like pimecrolimus, fromthe ascomycin class macrolactam, are used in some cases forimmunosuppression [48]. A monobenzone, 4-(Benzyloxy) phenolis used as a topical drug for medical depigmentation, which in caseof extensive vitiligo, can be used to get rid of the remainingmelanins, and to create a uniform melanin-free skin [49].Unfortunately, none of these drugs or surgeries are side effect-free or affordable to all vitiligo patients. In this regard, a number ofalternative medications have been suggested, such as the extractsfrom maidenhair tree (Ginkgo biloba) [50], flame vine (Pyrostegiavenusta) [51] and tropical fern (Polypodium leucotomos) [52,53].These botanical products cannot intervene at molecular level, butprotect from photo-aging. Khellin (a natural furochromonevasodilator) 4% ointment, as a photosensitizer, has shown somedegree of benefits [52,54,55]. Vitamins (B12, C, and E, folic acid)and minerals (zinc) are supposed to be beneficial for vitiligoalleviation [52,53]. Zinc being an antioxidant component, and anti-apoptotic factor, is suggested to be a skin favorable supplement[56]. The scope of amino acid L-phenylalanine as oral and topicaltherapy has been met with side-effect-free success [57].
However, for a disease that affects one among every hundredpeople, the existing therapeutic options are not efficacious enough.So, the molecular mechanisms of vitiligo need to be understoodprecisely.
A number of high-quality reviews focusing on different aspectsof this disease, such as clinical variations, pathological mecha-nisms, therapeutic modalities etc. have been published [18,58].This review discusses the latest developments on pertinent aspectsof this disease, and suggests hypotheses which might be examinedfor a more efficacious treatment. Cochrane, MEDLINE, Embase,Pubmed databases have been referred to for the scientific literaturediscussed here.
1.1. Mechanisms of pathogenesis
Decades of intense research has led to the accumulation ofimmense insights on vitiligo. However, given its multifactorial,and multi-genic attributes, much remains to be unraveled. Asynopsis of the key findings has been outlined below, beforeprobing deeper.
Melanocytes, the highly differentiated, dendritic-shaped, pig-ment-producing cells of the follicular and interfollicular epidermis,produce a specialized lysosome-related organelle melanosome(others being lytic granules, MHC class II compartments, platelet-dense granules, azurophil granules, basophil granules etc.) [59].Within the melanosome, melanin pigments are synthesized by
Fig. 1. Melanogenesis steps in melanocytes.
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melanogenesis [60] (Fig. 1). The compartmentalization of melano-some has been explained as a way to protect the cell frombyproducts of melanogenesis process, such as quinines andhydrogen peroxide [61]. Mature melanosomes are transferred tothe keratinocytes [61]. Melanocytes interact with and areinfluenced by keratinocytes and dermal fibroblasts, via cell-cellcontacts. Their secreted factors like stem cell factor (SCF), andneuregulin 1 (NRG1) regulate the properties of melanocytes. Self-secreted factors as interleukin-1 (IL-1), interleukin-1 (IL-6) andtumor necrosis factor-alpha (TNF-a) inhibit melanogenesis, whilefactors like eicosanoids and a-melanocyte-stimulating hormone(a-MSH) enhance melanin synthesis [61]. For detailed andinsightful reviews on the biology and traits of melanocytes, apublished article can be referred to [61].
Melanocytes are susceptible to oxidative stress, viral infec-tions, and are continuously replaced [62]. Immune-mediateddestruction of melanocytes following melanoma has beenobserved [63].
So, sudden onset of melanocyte apoptosis in vitiligo can bemultifactorial, driven by trauma, hormonal changes, puberty,pregnancy, diet, lifestyle assaults etc. [64]. Environmental influ-ences, apart from genetic predisposition leads to altered immunity,which recruits auto-antibodies against self-tissue (in this casemelanocytes) [65]. The key mechanisms of vitiligo development,orchestrated by the interaction between various biologicalcomponents, have been discussed here.
1.2. The role of ACTH and MSH in vitiligo development
Many skin disorders are associated with increased numbers ofactivated mast cells, and are aggravated by stress. The stressedmilieu leads to free radicals pooling, and provokes acidosis, whichlead to endocrine perturbation [66]. Among other hormones
responding to stress, peptide corticotrophin or ACTH (Adrenocor-ticotropic hormone) is a prominent one.
Stress causes the release of corticotropin-releasing factor (CRF)from brain hypothalamus and skin. This peptide hormone binds tobrain (pituitary) receptors. A study has shown that CRH increasesskin vascular permeability and mast cell activation [67]. Binding ofCRH to the receptors stimulates adenylate cyclase followed byactivation of cAMP pathway. Subsequently, polypeptide tropichormone ACTH is secreted from the anterior pituitary, whichstimulates adrenal cortex to produce glucocorticoid. So, ACTH is anubiquitous component of hypothalamic-pituitary-adrenal (HPA)axis [68,69]. ACTH is vital for steroidogenesis [70] and stimulatesthe adrenal cortex to produce cortisol, a glucocorticoid [71].Proopiomelanocortin (POMC) can be processed to ACTH andmelanocortin peptides by serine protease activity [71,72]. Vaso-pressin binds to receptors in pituitary gland, which activatesphospholipase C. The activated enzyme stimulates protein kinase Cwhich regulates ACTH [73]. Melanin synthesis is regulated bya-MSH elaborated from POMC [72]. So, it can be gathered thatmelanin synthesis is a process regulated by an array of hormones,and the disruption of any of them can interrupt the pigmentgenesis.
1.3. The role of thyroid gland hormones in vitiligo pathogenesis
Among their myriad of autoimmune pathologies, thyroiddiseases affect skin too, as observed in the form of conditionssuch as dermatoses (dermatitis herpetiformis), urticaria, andalopecia areata (loss of hair on scalp and other parts of the body),including vitiligo [74]. The correlation of vitiligo with the thyroidhormone is very strong. It has been suggested that vitiligo is amanifestation of thyroid disturbance (dysthyroidism) [75]. Gener-alized vitiligo is linked to autoimmune thyroid disease like
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Hashimoto's disease and Graves' disease [21]. TSH (thyroid-stimulating hormone) or thyrotropin is a dimeric glycoproteinhormone. Its globulin chains (alpha and beta) are approximately140aa long and are glycosylated. The b chain has a cysteine-knotdomain. By SMART (Simple Modular Architecture Research Tool)annotation of this chain, it was found to have a GHB (glycoproteinhormone beta chain homologues) domain [76]. BLAST (Basic LocalAlignment Search Tool) analysis of this chain showed the presenceof its protein homolog in arthropods (deer tick (Ixodes scapularis),red flour beetle (Tribolium castaneum) etc.) and echinoderms(purple sea urchin (Strongylocentrotus purpuratus)), apart fromchordates. In the above-mentioned invertebrates, the GHB domainoccurred with LRR (Leucine-rich repeats) and FBOX (a receptor forubiquitination targets) domains. Further annotation of the GHBdomain in other vertebrates showed that this domain is part of thelargest mammalian protein titin (connectin), a sarcomeric protein[76]. Titin occurs in cardiac muscle sacromeres, giving it therequired elasticity [77]. It is a substrate of Ca2+-dependentproteases, acts as sensor and regulates actin-myosin interactionsin muscles [78]. It occurs in multiple isoforms (dominant are N2Band N2BA), variation of which is accelerated in adaptive andpathological conditions. Also, its modified state (such as phos-phorylated) has been linked to vascular diseases like ischemiccardiomyopathy, aortic stenosis etc. [79,80]. Thyroglobulin is thesubstrate for the synthesis of thyroid hormones, which undergoesiodination at tyrosine residues to form the hormones [81].
Instances of chronic urticaria, and vitiligo have been found to besignificantly higher in autoimmune hypothyroidism patients thanin the control group [82]. Also, Graves’ disease (patient withexophthalmos (the bulging of the eye anteriorly out of the orbit))and vitiligo were found to be linked [83]. The link between vitiligoand autoimmune thyroid disease has been observed by Kumar
Fig. 2. The complex interactions between hormo
et al. [84]. Tyrosine kinase inhibitors can induce thyroid dysfunc-tion, decreasing iodine uptake by the thyroid gland [85].
1.4. Other important regulators
G-protein-coupled receptors (GPCRs), which initiate cellularsignaling, constitute the largest class of cell-surface localizedreceptors. GPCRs ligands include neurotransmitters (histamine,dopamine, norepinephrine, epinephrine, serotonin, and melato-nin), hormones (endothelins, and CRF), fatty acids (eicosanoids),phospholipids, odorants, photons, among others [86,87]. Theseligands interact with GPCRs and thus influence the activity ofmelanocytes, as the role of CRF has been discussed before.Cytoplasmic domains of activated GPCRs transduce signals toactivate G proteins [88].
The hormones involved in melanogenesis and vitiligo has beenpresented in Fig. 2. Apart from thyroid hormone, and ACTH, otherlesser-investigated factors with role in vitiligo pathogenesisinclude hormones, diet, cosmetics, and chemical allergens. Theprobable role of these factors has been hypothesized in theDiscussion section. All the cited factors play role in differentcombinations, depending on allelic makeup and environmentalexposure of the individual.
2. Discussion
The cumulative understanding of vitiligo is substantial. However,based on the published literature on vitiligo, some patterns havebeen observed, and certain lacunae have been identified.
Though it is reported that both genders are equally prone tovitiligo, it seems males are at higher risk. While thyroiddisturbance is more common in women [89], it is manifested
nes involved in melanogenesis and vitiligo.
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more in the form of infertility [90], rather than vitiligo. Does thatmean Y chromosome has role in expression of the vitiligo genes?No literature support is found to shed light on this assumption.Does estrogen (17b-estradiol) prevent vitiligo in females? An invitro study showed that estrogen can lead to melasma (grayish-brown facial pigmentation) development [91]. As melanocyteshave estrogen receptors (ERs), estrogen acts as ligands andincreases melanin pigment production [92]. Females of child-bearing age, due to high estrogen concentration might, be lessprone to vitiligo. This hypothesis ought to be investigated.
Lack of fertility and vitiligo are linked. But, it is still to bediscovered how they are associated. In male hypogonadism,testosterone hormone production is inadequate, which leads toinfertility [93]. A rodent model study showed that testosterone hasbeneficial effect on thyroid functions [94]. These findings can bepieced together to rationalize the connection between infertilityand vitiligo.
Melatonin is a pleiotropic hormone secreted by pineal gland(though it can be secreted from skin and hair follicles), whichprotects the skin against oxidative stress, including UV light [95]. L-tryptophan forms serotonin and melatonin, catalyzed by trypto-phan hydroxylase, serotonin N-acetyl-transferase, and hydroxyin-dole-O-methyltransferase [96,97]. Findings on the role ofmelatonin in vitiligo development via melanocye destruction isconflicting [98], with immense scope for investigation.
As in many other diseases, diet seems to play critical role invitiligo development [99,100]. Dietary habit is a critical trigger inthe expression of disease-bearing genes. As tyrosine is anessential component of thyroid hormone [101], is its deficiencyleading to thyroid malfunction? Or despite consumption of thetyrosine-rich foods, it is not metabolized and assimilated? Somefeedback loop might be inhibiting the incorporation of this aminoacid. Tyrosine amino acid-rich foods are particularly important inthis regard. Several of the commonly consumed foods like cheese(Parmesan), soy products (soy sauce), meat (beef, goat, chicken),fish, and nuts are rich in this amino acid. Tyrosine is the precursorof catecholamine-type neurotransmitters (neural signaling mol-ecules) such as dopamine, norepinephrine, epinephrine (adrena-line) etc. [102]. These neurotransmitters control both central andperipheral nervous systems. High tyrosine-foods are deemed toimprove cognition, attention, and emotional traits. In mice modelstudies, locomotor activity were restored to normalcy after L-tyrosine supplementation [103]. L-tyrosine forms melaninpigment as well, via melanogenesis [104]. This amino acid isconverted into neurotransmitters and pigment by tyrosinehydroxylase enzyme [105]. Several critical enzymes are inhibitedby their own substrates, leading to reduced enzyme activity as thesubstrate pools, by the mechanism of feedback inhibition[106,107]. D-3-phosphoglycerate dehydrogenase (substratehydroxypyruvic acid phosphate), and homocitrate synthase (L-lysine) are some examples of feedback loop inhibition [108,109]. Itpoints towards the possibility that excess tyrosine-rich diet mightbe a reason, that the enzyme activity is lowered and melaninsynthesis is affected. It has been observed that the consumptionof milk and whey protein often aggravates acne in adolescents.The reason has been cited as the growth factors in these dairyproducts which stimulate endogenous hormones [110]. Candairy-based foods be manipulating hormones to cause vitiligo?In western world, celiac disease, a result of gluten intolerance iswell-known as an inflammatory condition. However, in develop-ing countries, where food options are not broad, people keep onconsuming gluten-rich grains, despite enteric inflammations.They often mistake these signals as gastric ulcers or diabetes. Asceliac disease is an autoimmune manifestation of thyroid disorder[74], it might be hypothesized that, the gluten-rich diet might beincreasing the vulnerability of vitiligo-predisposed individuals. Is
alcohol or any other intoxication, and beverages act as vitiligotrigger? In India, females do not generally consume alcohols. Canit be linked to lower prevalence of vitiligo in them? Alcoholconsumption has been linked to a litany of skin-related issuessuch as psoriasis, rosacea, porphyria cutanea tardy (a subtype ofporphyria.), discoid eczema, post adolescent acne etc. [111].
Acne vulgaris is common skin problem of adolescents, causedby hormonal stimulation, leading to the obstruction of sebaceousglands and the induction of hyperkeratinization [112]. To get rid ofthe acnes, the sufferers often resort to cosmetics. Also, people oftenuse skin-whitening agents, which is likely to be manipulating withthe melanocyte functions. Evidences suggest that sunscreenlotions can cause psoriasis, as they block UV radiation known topossess antipsoriatic effect via calcitriol (a form of vitamin D)synthesis [113]. Ethanol is a constituent of a number of toiletryproducts (deodorant, moisturizer, mouthwashes, hairsprays, bodywash etc.), prolonged topical use of which might have health risks[114]. A questionnaire-based study reports that the frequent use ofalcohol gel for infection control led to skin problems, such as skinirritation or contact dermatitis, in hospital staff [115]. The alcohol-related issues are more conspicuous especially in individuals withan aldehyde dehydrogenase (ALDH) deficiency. Absence of thisenzyme prevents acetaldehyde detoxification [116]. It is very muchlikely that alcohol might be triggering vitiligo as well. All theseaspects are worthy of investigation.
Allergens, when exposed to for prolonged period, lead toinflammation, which has adverse effect on neural circuits.Perturbed neural signal can destroy melanocytes. Orthopedicimplants have alloy metal or bone cement, which can provokeallergic reactions. The chemicals like acrylate, and peroxide in thebiomaterials might be activating immune system, setting the stagefor vitiligo [117].
In many homozygotic/inbreeding (mating between two relatedindividuals) communities (as seen in a Romanian community),vitiligo prevalence is higher [118]. Does that mean the retention ofthe recessive genes increase the expression probability of thevitiligo phenotype? Other inbreeding-related diseases as sickle cellanemia and b-thalassemia in India are well-studied [119]. Vitiligoruns in families. It raises the question if the genes bearing thevitiligo allele are dominant? It should be investigated, if epistasisdetermines the outcome?
There is no dispute that vitiligo is the result of aggravatedthyroid function. Hence, thyroid treatment might help recede andreverse vitiligo. Better management of vitiligo can be achieved bymetabolomics studies (through mass spectrometry (MS) andnuclear magnetic resonance (NMR)). Patient biomarkers charac-terized by these omic technologies can indicate the upregulatedpathways. Though in silico methods have already identified themajor suspect genes, there is scope of further understanding usingthese tools. These algorithms can predict triggers, symptoms,genetic basis, linkage, and therapeutic success.
Oxidative stress plays a major role in the pathogenesis of avariety of acute and chronic diseases. Measurement of theoxidative stress-related end products such as structural isomersof the physiological para-tyrosine (namely meta- and ortho-tyrosine, that are oxidized derivatives of phenylalanine) can shedsome light on the puzzle of vitiligo pathology [120]. A bloodanalysis study has already shown the reduced erythrocytic orsystemic level of glutathione (GSH) in vitiligo patients [121].
It can be inferred that vitiligo, like other diseases, aremultifactorial. Triggers can be different, depending on theparameters such as age, gender, health status and co-morbidities.Any of these factors or their combinations are provoking genesresponsible for melanocyte homeostasis.
Early detection might be helpful in curbing or halting vitiligobetter. A number of other diseases have been observed to precede
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or co-occur with vitiligo, which might be considered as a warningsign. Though, they may not always be pathologically-linked tovitiligo, but might be a side effect of steroid therapy (such asglaucoma (increased intraocular pressure) was observed in vitiligopatient) [122].
In view of the fact that currently vitiligo has no guaranteedcure, the search of pathogenic causes and preventive measuresmust be continued. Diverse epidemiological cohorts should beused for better understanding of the role of genes in onset andprogression of this disease. Also, psychological consulting canhelp patients cope with vitiligo. Patients should be cognizant ofthe irreversible risks associated steroids and drug-herb inter-actions, and must not use them on their own. Such attempts onlyaggravate the pathologies. Vulnerable people should be awarebased on their familial genetic history and practice moderation indiet and lifestyle so as not to trigger the disease. For all thesemeasures of lifestyle correction, self-education is critical. Withconvenient digital technology at everyone’s disposal, it should notbe difficult.
3. Conclusion
Vitiligo, like an array of other diseases, is an inflammatory,immune-activation-driven disease. Human system is complex andthe total gene pool has myriad alleles. The allelic makeupcombined with variable triggers determine the pathological courseof any disease, including vitiligo. As there can be inimitablepermutations and combinations, generalizing inferences aredaunting. However, continued investigations based on theabove-formulated hypotheses can improve our grasp over thisskin disease.
Compliance with ethical standards
The authors declare that there is no competing interest. Thiswork does not involve human participants or animal models.
References
[1] G.S. Cooper, M.L.K. Bynum, E.C. Somers, Recent insights in the epidemiologyof autoimmune diseases: improved prevalence estimates and understandingof clustering of diseases, J. Autoimmun. 33 (2009) 197–207, doi:http://dx.doi.org/10.1016/j.jaut.2009.09.008.
[2] R. Falabella, Vitiligo and the melanocyte reservoir, Indian J. Dermatol. 54(2009) 313–318, doi:http://dx.doi.org/10.4103/0019-5154.57604.
[3] H.T. Pandve, Vitiligo: is it just a dermatological disorder? Indian J. Dermatol.53 (2008) 40–41, doi:http://dx.doi.org/10.4103/0019-5154.39745.
[4] A.J. Kanwar, M.S. Kumaran, Childhood vitiligo: treatment paradigms, Indian J.Dermatol. 57 (2012) 466–474, doi:http://dx.doi.org/10.4103/0019-5154.103067.
[5] M. Sukan, F. Maner, The problems in sexual functions of vitiligo and chronicurticaria patients, J. Sex Marital Ther. 33 (2007) 55–64, doi:http://dx.doi.org/10.1080/00926230600998482.
[6] F. Van Driessche, N. Silverberg, Current management of pediatric vitiligo,Paediatr. Drugs 17 (2015) 303–313, doi:http://dx.doi.org/10.1007/s40272-015-0135-3.
[7] P. Prakash, D.M. Thappa, A clinical study of the spectrum of vitiligo in childrenversus adults and its associations, Online J. 4 (2013) 250–251, doi:http://dx.doi.org/10.4103/2229-5178.115539.
[8] M. Brenner, V.J. Hearing, Modifying skin pigmentation – approaches throughintrinsic biochemistry and exogenous agents, Drug Discov. Today. Dis. Mech.5 (2008) e189–e199, doi:http://dx.doi.org/10.1016/j.ddmec.2008.02.001.
[9] K. Ezzedine, H.W. Lim, T. Suzuki, I. Katayama, I. Hamzavi, C.C.E. Lan, B.K. Goh,T. Anbar, C. Silva de Castro, A.Y. Lee, D. Parsad, N. van Geel, I.C. Le Poole, N.Oiso, L. Benzekri, R. Spritz, Y. Gauthier, S.K. Hann, M. Picardo, A. Taieb, Vitiligoglobal issue consensus conference panelists, revised classification/nomenclature of vitiligo and related issues: the vitiligo global issuesconsensus conference, Pigment Cell Melanoma Res. 25 (2012) E1–E13, doi:http://dx.doi.org/10.1111/j.1755-148X.2012.00997.x.
[10] R. Matin, Vitiligo, BMJ Clin. Evid. 2008 (2008) http://www.ncbi.nlm.nih.gov/pubmed/19450313 (accessed August 17, 2016).
[11] L. Guerra, E. Dellambra, S. Brescia, D. Raskovic, Vitiligo: pathogenetichypotheses and targets for current therapies, Curr. Drug Metab. 11 (2010)
[12] R.A. Spritz, Recent progress in the genetics of generalized vitiligo, J. Genet.Genomics 38 (2011) 271–278, doi:http://dx.doi.org/10.1016/j.jgg.2011.05.005.
[13] J.-H. Park, M.-Y. Jung, J.-H. Lee, J.-M. Yang, D.-Y. Lee, K.K. Park, Clinical courseof segmental vitiligo: a retrospective study of eighty-seven patients, Ann.Dermatol. 26 (2014) 61–65, doi:http://dx.doi.org/10.5021/ad.2014.26.1.61.
[14] S.A. Ismail, D.S. Sayed, L.N. Abdelghani, Vitiligo management strategy inJeddah, Saudi Arabia as reported by dermatologists and experienced bypatients, J. Dermatolog. Treat. 25 (2014) 205–211, doi:http://dx.doi.org/10.3109/09546634.2012.762638.
[15] A. Stanimirovic, M. Kovacevic, I. Korobko, M. Šitum, T. Lotti, Combinedtherapy for resistant vitiligo lesions: NB-UVB, microneedling, and topicallatanoprost, showed no enhanced efficacy compared to topical latanoprostand NB-UVB, Dermatol. Ther. 29 (2016) 312–316, doi:http://dx.doi.org/10.1111/dth.12363.
[16] A.J. Kanwar, M.S. Kumaran, Childhood vitiligo: treatment paradigms, Indian J.Dermatol. 57 (2012) 466–474, doi:http://dx.doi.org/10.4103/0019-5154.103067.
[17] S. Di Nuzzo, A. Masotti, Depigmentation therapy in vitiligo universalis withcryotherapy and 4-hydroxyanisole, Clin. Exp. Dermatol. 35 (2010) 215–216,doi:http://dx.doi.org/10.1111/j.1365-2230.2009.03412.x.
[18] R. Yaghoobi, M. Omidian, N. Bagherani, Vitiligo: a review of the publishedwork, J. Dermatol. 38 (2011) 419–431 http://www.ncbi.nlm.nih.gov/pubmed/21667529 (accessed July 11, 2016).
[19] B. Doshi, S. Mahajan, U.S. Khopkar, V. Kharkar, P. Agarwal, Epidermotropicmetastatic melanoma with perilesional depigmentation in an Indian male,Indian J. Dermatol. 58 (2013) 396–399, doi:http://dx.doi.org/10.4103/0019-5154.117323.
[20] J.C. de Barros, C.D.S. Machado Filho, L.C. Abreu, J.A. de Barros, F.M. Paschoal,M.T. Nomura, E. Marques, L.C. Martins, A study of clinical profiles of vitiligo indifferent ages: an analysis of 669 outpatients, Int. J. Dermatol. 53 (2014) 842–848, doi:http://dx.doi.org/10.1111/ijd.12055.
[22] H.A. Al-Shobaili, Update on the genetics characterization of vitiligo, Int. J.Health Sci. (Qassim) 5 (2011) 167–179 http://www.ncbi.nlm.nih.gov/pubmed/23267294 (accessed July 11, 2016).
[23] A.G. Smith, R.A. Sturm, Multiple genes and locus interactions in susceptibilityto vitiligo, J. Invest. Dermatol. 130 (3) (2010) 643–645.
[24] S.R. Jin Y1, S.L. Riccardi, K. Gowan, P.R. Fain, Fine-mapping of vitiligosusceptibility loci on chromosomes 7 and 9 and interactions with NLRP1(NALP1), J. Invest. Dermatol. 130 (3) (2010) 774–783.
[25] G. Meyer, K. Badenhoop, Autoimmune regulator (AIRE) gene on chromosome21: Implications for autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) and more common manifestations ofendocrine autoimmunity, J. Endocrinol. Invest. 25 (2002) 804–811, doi:http://dx.doi.org/10.1007/BF03345516.
[26] H.J. Williams, M.J. Owen, M.C. O’Donovan, Is COMT a susceptibility gene forschizophrenia? Schizophr. Bull. 33 (2007) 635–641, doi:http://dx.doi.org/10.1093/schbul/sbm019.
[27] Z. Zhang, S.-X. Xu, F.-Y. Zhang, X.-Y. Yin, S. Yang, F.-L. Xiao, W.-H. Du, J.-F.Wang, Y.-M. Lv, H.-Y. Tang, X.-J. Zhang, The analysis of genetics and associatedautoimmune diseases in Chinese vitiligo patients, Arch. Dermatol. Res. 301(2009) 167–173, doi:http://dx.doi.org/10.1007/s00403-008-0900-z.
[28] A. Alkhateeb, P.R. Fain, A. Thody, D.C. Bennett, R.A. Spritz, Epidemiology ofvitiligo and associated autoimmune diseases in Caucasian probands and theirfamilies, Pigment Cell Res. 16 (2003) 208–214 http://www.ncbi.nlm.nih.gov/pubmed/12753387 (accessed July 11, 2016).
[29] G. Laberge, C.M. Mailloux, K. Gowan, P. Holland, D.C. Bennett, P.R. Fain, R.A.Spritz, Early disease onset and increased risk of other autoimmune diseasesin familial generalized vitiligo, Pigment Cell Res. 18 (2005) 300–305, doi:http://dx.doi.org/10.1111/j.1600-0749.2005.00242.x.
[30] S.K. Nath, J.A. Kelly, B. Namjou, T. Lam, G.R. Bruner, R.H. Scofield, C.E. Aston, J.B. Harley, Evidence for a susceptibility gene, SLEV1, on chromosome 17p13 infamilies with vitiligo-related systemic lupus erythematosus, Am. J. Hum.Genet. 69 (2001) 1401–1406, doi:http://dx.doi.org/10.1086/324470.
[31] Z. Shahmoradi, J. Najafian, F.F. Naeini, F. Fahimipour, Vitiligo andautoantibodies of celiac disease, Int. J. Prev. Med. 4 (2013) 200–203 http://www.ncbi.nlm.nih.gov/pubmed/23543680 (accessed August 17, 2016).
[32] J.I. Silverberg, N.B. Silverberg, Vitiligo disease triggers: psychologicalstressors preceding the onset of disease, Cutis 95 (2015) 255–262 http://www.ncbi.nlm.nih.gov/pubmed/26057504 (accessed August 17, 2016).
[33] H. Xie, F. Zhou, L. Liu, G. Zhu, Q. Li, C. Li, T. Gao, Vitiligo: how do oxidativestress-induced autoantigens trigger autoimmunity? J. Dermatol. Sci. 81(2016) 3–9, doi:http://dx.doi.org/10.1016/j.jdermsci.2015.09.003.
[34] A.R. Hossani-Madani, R.M. Halder, Topical treatment and combinationapproaches for vitiligo: new insights, new developments, G. Ital. DiDermatologia E Venereol. Organo Uff. Soc. Ital. Di Dermatologia E Sifilogr. 145(2010) 57–78 http://www.ncbi.nlm.nih.gov/pubmed/20197746 (accessedAugust 17, 2016).
[35] A. Abraham, G. Roga, Topical steroid-damaged skin, Indian J. Dermatol. 59(2014) 456–459, doi:http://dx.doi.org/10.4103/0019-5154.139872.
S. Patel et al. / Biomedicine & Pharmacotherapy 92 (2017) 501–508 507
[36] A. Coondoo, M. Phiske, S. Verma, K. Lahiri, Side-effects of topical steroids: along overdue revisit, Indian Dermatol. Online J. 5 (2014) 416–425, doi:http://dx.doi.org/10.4103/2229-5178.142483.
[37] T. Lotti, G. Buggiani, M. Troiano, G.B. Assad, J. Delescluse, V. De Giorgi, J.Hercogova, Targeted and combination treatments for vitiligo. Comparativeevaluation of different current modalities in 458 subjects, Dermatol. Ther. 21(Suppl. 1) (2008) S20–S26, doi:http://dx.doi.org/10.1111/j.1529-8019.2008.00198.x.
[38] S. Kandaswamy, N. Akhtar, S. Ravindran, S. Prabhu, S.D. Shenoi, Phototherapyin vitiligo: assessing the compliance, response and patient’s perception aboutdisease and treatment, Indian J. Dermatol. 58 (2013) 325, doi:http://dx.doi.org/10.4103/0019-5154.113944.
[39] R. Wong, A.N. Lin, Efficacy of topical calcineurin inhibitors in vitiligo, Int. J.Dermatol. 52 (2013) 491–496, doi:http://dx.doi.org/10.1111/j.1365-4632.2012.05697.x.
[40] N.J. Lee, M. McDonagh, B. Chan, K. Peterson, S. Thakurta, Drug Class Review:Topical Calcineurin Inhibitors, Oregon Health & Science University, 2008,2017 http://www.ncbi.nlm.nih.gov/pubmed/20496106 (accessed August 17,2016).
[41] T. Song, Z. Rao, Q. Tan, Y. Qiu, J. Liu, Z. Huang, X. Wang, T. Lin, Calcineurininhibitors associated posterior reversible encephalopathy syndrome in solidorgan transplantation: report of 2 cases and literature review, Medicine(Baltimore) 95 (2016) e3173, doi:http://dx.doi.org/10.1097/MD.0000000000003173.
[42] K.N. Sarveswari, Cosmetic camouflage in vitiligo, Indian J. Dermatol. 55(2010) 211–214, doi:http://dx.doi.org/10.4103/0019-5154.70663.
[43] N. Rajatanavin, S. Suwanachote, S. Kulkollakarn, Dihydroxyacetone: a safecamouflaging option in vitiligo, Int. J. Dermatol. 47 (2008) 402–406, doi:http://dx.doi.org/10.1111/j.1365-4632.2008.03356.x.
[44] A.B. Petersen, H.C. Wulf, R. Gniadecki, B. Gajkowska, Dihydroxyacetone, theactive browning ingredient in sunless tanning lotions, induces DNA damage,cell-cycle block and apoptosis in cultured HaCaT keratinocytes, Mutat. Res.560 (2004) 173–186, doi:http://dx.doi.org/10.1016/j.mrgentox.2004.03.002.
[45] C. Hossain, D.A. Porto, I. Hamzavi, H.W. Lim, Camouflaging agents for vitiligopatients, J. Drugs Dermatol. 15 (2016) 384–387 http://www.ncbi.nlm.nih.gov/pubmed/27050692 (accessed August 17, 2016).
[46] A.K. Singh, D. Karki, Micropigmentation: tattooing for the treatment of lipvitiligo, J. Plast. Reconstr. Aesthet. Surg. 63 (2010) 988–991, doi:http://dx.doi.org/10.1016/j.bjps.2009.03.013.
[47] C. Wassef, A. Lombardi, S. Khokher, B.K. Rao, Vitiligo surgical, laser, andalternative therapies: a review and case series, J. Drugs Dermatol. 12 (2013)685–691 http://www.ncbi.nlm.nih.gov/pubmed/23839187 (accessed July 11,2016).
[48] N. Sendur, G. Karaman, N. Saniç, E. Savk, Topical pimecrolimus: a new horizonfor vitiligo treatment? J. Dermatolog. Treat. 17 (2006) 338–342, doi:http://dx.doi.org/10.1080/09546630601028711.
[49] O.M. Rordam, E.W. Lenouvel, M. Maalo, Successful treatment of extensivevitiligo with monobenzone, J. Clin. Aesthet. Dermatol. 5 (2012) 36–39 http://www.ncbi.nlm.nih.gov/pubmed/23277803 (accessed July 11, 2016).
[50] O. Szczurko, N. Shear, A. Taddio, H. Boon, Ginkgo biloba for the treatment ofvitilgo vulgaris: an open label pilot clinical trial., BMC Complement, Altern.Med. 11 (2011) 21, doi:http://dx.doi.org/10.1186/1472-6882-11-21.
[51] C.G. Moreira, L.Z.B. Carrenho, P.L. Pawloski, B.S. Soley, D.A. Cabrini, M.F. Otuki,Pre-clinical evidences of Pyrostegia venusta in the treatment of vitiligo, J.Ethnopharmacol. 168 (2015) 315–325, doi:http://dx.doi.org/10.1016/j.jep.2015.03.080.
[52] B.E. Cohen, N. Elbuluk, E.W. Mu, S.J. Orlow, Alternative systemic treatmentsfor vitiligo: a review, Am. J. Clin. Dermatol. 16 (2015) 463–474, doi:http://dx.doi.org/10.1007/s40257-015-0153-5.
[53] M. Nestor, V. Bucay, V. Callender, J.L. Cohen, N. Sadick, H. Waldorf,Polypodium leucotomos as an adjunct treatment of pigmentary disorders,J. Clin. Aesthet. Dermatol. 7 (2014) 13–17 http://www.ncbi.nlm.nih.gov/pubmed/24688621 (accessed July 11, 2016).
[54] D. Vedaldi, S. Caffieri, F. Dall’Acqua, L. Andreassi, L. Bovalini, P. Martelli,Khellin, a naturally occurring furochromone, used for thephotochemotherapy of skin diseases: mechanism of action, Farmaco. Sci. 43(1988) 333–346 http://www.ncbi.nlm.nih.gov/pubmed/3203737 (accessedJuly 11, 2016).
[55] R. Saraceno, S.P. Nisticò, E. Capriotti, S. Chimenti, Monochromatic excimerlight 308ònm in monotherapy and combined with topical khellin 4% in thetreatment of vitiligo: a controlled study, Dermatol. Ther. 22 (2009) 391–394,doi:http://dx.doi.org/10.1111/j.1529-8019.2009.01252.x.
[56] N. Bagherani, R. Yaghoobi, M. Omidian, Hypothesis: zinc can be effective intreatment of vitiligo, Indian J. Dermatol. 56 (2011) 480–484, doi:http://dx.doi.org/10.4103/0019-5154.87116.
[57] F. Camacho, J. Mazuecos, Oral and topical L-phenylalanine, clobetasolpropionate, and UVA/sunlight–a new study for the treatment of vitiligo, J.Drugs Dermatol. 1 (2002) 127–131 http://www.ncbi.nlm.nih.gov/pubmed/12847735 (accessed August 17, 2016).
[58] A. Miniati, Z. Weng, B. Zhang, A.J. Stratigos, E. Nicolaidou, T.C. Theoharides,Neuro-immuno-endocrine processes in vitiligo pathogenesis, Int. J.Immunopathol. Pharmacol. 25 (2012) 1–7 http://www.ncbi.nlm.nih.gov/pubmed/22507311 (accessed July 12, 2016).
[59] E.C. Dell’Angelica, C. Mullins, S. Caplan, J.S. Bonifacino, Lysosome-relatedorganelles, FASEB J. 14 (2000) 1265–1278 http://www.ncbi.nlm.nih.gov/pubmed/10877819 (accessed August 19, 2016).
[60] J.P. Ebanks, R.R. Wickett, R.E. Boissy, Mechanisms regulating skinpigmentation: the rise and fall of complexion coloration, Int. J. Mol. Sci. 10(2009) 4066–4087, doi:http://dx.doi.org/10.3390/ijms10094066.
[61] M. Cichorek, M. Wachulska, A. Stasiewicz, A. Tymi�nska, Skin melanocytes:biology and development, Postepy Dermatologii I Alergol 30 (2013) 30–41,doi:http://dx.doi.org/10.5114/pdia.2013.33376.
[62] S. Wang, D. Liu, W. Ning, A. Xu, Cytosolic dsDNA triggers apoptosis and pro-inflammatory cytokine production in normal human melanocytes, Exp.Dermatol. 24 (2015) 298–300, doi:http://dx.doi.org/10.1111/exd.12621.
[63] C. Yee, J.A. Thompson, P. Roche, D.R. Byrd, P.P. Lee, M. Piepkorn, K. Kenyon, M.M. Davis, S.R. Riddell, P.D. Greenberg, Melanocyte destruction after antigen-specific immunotherapy of melanoma: direct evidence of t cell-mediatedvitiligo, J. Exp. Med. 192 (2000) 1637–1644 http://www.ncbi.nlm.nih.gov/pubmed/11104805 (accessed August 20, 2016).
[64] R. Czajkowski, K. Meci�nska-Jundziłł, Current aspects of vitiligo genetics,Postepy Dermatologii I Alergol 31 (2014) 247–255, doi:http://dx.doi.org/10.5114/pdia.2014.43497.
[65] M.W. Kroon, E.H. Kemp, B.S. Wind, G. Krebbers, J.D. Bos, D.J. Gawkrodger, A.Wolkerstorfer, J.P.W. van der Veen, R.M. Luiten, Melanocyte antigen-specificantibodies cannot be used as markers for recent disease activity in patientswith vitiligo, J. Eur. Acad. Dermatol. Venereol. 27 (2013) 1172–1175, doi:http://dx.doi.org/10.1111/j.1468-3083.2012.04501.x.
[66] K.U. Schallreuter, M.A.E.L. Salem, S. Holtz, A. Panske, Basic evidence forepidermal H2O2/ONOO?mediated oxidation/nitration in segmental vitiligois supported by repigmentation of skin and eyelashes after reduction ofepidermal H2O2 with topical NB-UVB-activated pseudocatalase PC-KUS,FASEB J. 27 (2013) 3113–3122, doi:http://dx.doi.org/10.1096/fj.12-226779.
[67] J. Donelan, W. Boucher, N. Papadopoulou, M. Lytinas, D. Papaliodis, P. Dobner,T.C. Theoharides, Corticotropin-releasing hormone induces skin vascularpermeability through a neurotensin-dependent process, Proc. Natl. Acad. Sci.103 (2006) 7759–7764, doi:http://dx.doi.org/10.1073/pnas.0602210103.
[68] S.M. Smith, W.W. Vale, The role of the hypothalamic-pituitary-adrenal axis inneuroendocrine responses to stress, Dialogues Clin. Neurosci. 8 (2006) 383–395 http://www.ncbi.nlm.nih.gov/pubmed/17290797 (accessed July 12,2016).
[69] V.B. Risbrough, M.B. Stein, Role of corticotropin releasing factor in anxietydisorders: a translational research perspective, Horm. Behav. 50 (2006) 550–561, doi:http://dx.doi.org/10.1016/j.yhbeh.2006.06.019.
[70] N. Gallo-Payet, 60 years of POMC: adrenal and extra-adrenal functions ofACTH, J. Mol. Endocrinol. 56 (2016) T135–T156, doi:http://dx.doi.org/10.1530/JME-15-0257.
[71] K. Rousseau, S. Kauser, L.E. Pritchard, A. Warhurst, R.L. Oliver, A. Slominski, E.T. Wei, A.J. Thody, D.J. Tobin, A. White, Proopiomelanocortin (POMC), theACTH/melanocortin precursor, is secreted by human epidermal keratinocytesand melanocytes and stimulates melanogenesis, FASEB J. 21 (2007) 1844–1856, doi:http://dx.doi.org/10.1096/fj.06-7398com.
[72] H. Yamamoto, T. Yamane, K. Iguchi, K. Tanaka, A. Iddamalgoda, K. Unno, M.Hoshino, A. Takeda, Melanin production through novel processing ofproopiomelanocortin in the extracellular compartment of the auricular skinof C57BL/6 mice after UV-irradiation, Sci. Rep. 5 (2015) 14579, doi:http://dx.doi.org/10.1038/srep14579.
[73] S.M. Smith, W.W. Vale, The role of the hypothalamic-pituitary-adrenal axis inneuroendocrine responses to stress, Dialogues Clin. Neurosci. 8 (2006) 383–395 http://www.ncbi.nlm.nih.gov/pubmed/17290797 (accessed August 20,2016).
[75] N. Puri, A study on cutaneous manifestations of thyroid disease, Indian J.Dermatol. 57 (2012) 247–248, doi:http://dx.doi.org/10.4103/0019-5154.96227.
[76] C.P. Ponting, J. Schultz, F. Milpetz, P. Bork, SMART: identification andannotation of domains from signalling and extracellular protein sequences,Nucleic Acids Res. 27 (1999) 229–232, doi:http://dx.doi.org/10.1093/nar/27.1.229.
[77] K. Trombitás, J.P. Jin, H. Granzier, The mechanically active domain of titin incardiac muscle, Circ. Res. 77 (1995) 856–861 http://www.ncbi.nlm.nih.gov/pubmed/7554133 (accessed August 21, 2016).
[78] N. Niederländer, F. Raynaud, C. Astier, P. Chaussepied, Regulation of the actin-myosin interaction by titin, Eur. J. Biochem. 271 (2004) 4572–4581, doi:http://dx.doi.org/10.1111/j.1432-1033.2004.04429.x.
[79] R. Castro-Ferreira, R. Fontes-Carvalho, I. Falcão-Pires, A.F. Leite-Moreira, Therole of titin in the modulation of cardiac function and its pathophysiologicalimplications, Arq. Bras. Cardiol. 96 (2011) 332–339 http://www.ncbi.nlm.nih.gov/pubmed/21359482 (accessed July 11, 2016).
[80] I.M. Vikhlyantsev, Z.A. Podlubnaya, New titin (connectin) isoforms and theirfunctional role in striated muscles of mammals: facts and suppositions,Biochem. Biokhimiia. 77 (2012) 1515–1535, doi:http://dx.doi.org/10.1134/S0006297912130093.
[81] F. Ahad, S.A. Ganie, Iodine, Iodine metabolism and Iodine deficiency disordersrevisited, Metab 14 (2010) 13–17 http://www.ncbi.nlm.nih.gov/pubmed/21448409 (accessed July 11, 2016).
[82] G.S. Artantaş S, Gül U, Kiliç A, Skin findings in thyroid diseases, (n.d.).[83] B. Prindaville, S.A. Rivkees, Incidence of vitiligo in children with Graves’
disease and Hashimoto’s thyroiditis, Int. J. Pediatr. Endocrinol. 2011 (2011) 18,doi:http://dx.doi.org/10.1186/1687-9856-2011-18.
508 S. Patel et al. / Biomedicine & Pharmacotherapy 92 (2017) 501–508
[84] K.V.S.H. Kumar, S. Priya, R. Sharma, U. Kapoor, M. Saini, Y.S. Bisht,Autoimmune thyroid disease in patients with vitiligo: prevalence study inIndia, Endocr. Pract. 18 (2012) 194–199, doi:http://dx.doi.org/10.4158/EP11205.OR.
[85] H. Ahmadieh, I. Salti, Tyrosine kinase inhibitors induced thyroid dysfunction:a review of its incidence, pathophysiology, clinical relevance, and treatment,Biomed Res. Int. 2013 (2013) 725410, doi:http://dx.doi.org/10.1155/2013/725410.
[86] D. Julius, J. Nathans, Signaling by sensory receptors, Cold Spring Harb.Perspect. Biol. 4 (2012) a005991, doi:http://dx.doi.org/10.1101/cshperspect.a005991.
[87] B. Alberts, A. Johnson, J. Lewis, M. Raff, K. Roberts, P. Walter, SignalingThrough G-Protein-Linked Cell-Surface Receptors, (2002) http://www.ncbi.nlm.nih.gov/books/NBK26912/ (accessed June 8, 2015).
[88] J.A. Carlson, G.P. Linette, A. Aplin, B. Ng, A. Slominski, Melanocyte receptors:clinical implications and therapeutic relevance, Dermatol. Clin. 25 (2007)541–557, doi:http://dx.doi.org/10.1016/j.det.2007.06.005 viii–ix.
[89] A. Gessl, R. Lemmens-Gruber, A. Kautzky-Willer, Thyroid disorders, Handb.Exp. Pharmacol. (2012) 361–386, doi:http://dx.doi.org/10.1007/978-3-642-30726-3_17.
[90] I. Verma, R. Sood, S. Juneja, S. Kaur, Prevalence of hypothyroidism in infertilewomen and evaluation of response of treatment for hypothyroidism oninfertility, Int. J. Appl. Basic Med. Res. 2 (2012) 17–19, doi:http://dx.doi.org/10.4103/2229-516X.96795.
[91] H.Y. Kang, J.-P. Ortonne, What should be considered in treatment of melasma,Ann. Dermatol. 22 (2010) 373–378, doi:http://dx.doi.org/10.5021/ad.2010.22.4.373.
[92] C.A. Natale, E.K. Duperret, J. Zhang, R. Sadeghi, A. Dahal, K.T. O’Brien, R.Cookson, J.D. Winkler, T.W. Ridky, Sex steroids regulate skin pigmentationthrough nonclassical membrane-bound receptors, Elife 5 (2016), doi:http://dx.doi.org/10.7554/eLife.15104.
[93] P. Kumar, N. Kumar, D.S. Thakur, A. Patidar, Male hypogonadism: symptomsand treatment, J. Adv. Pharm. Technol. Res. 1 (2010) 297–301, doi:http://dx.doi.org/10.4103/0110-5558.72420.
[94] Z. Bahrami, M. Hedayati, M. Taghikhani, F. Azizi, Effect of testosterone onthyroid weight and function in iodine deficient castrated rats, Horm. Metab.Res.=Horm. Und Stoffwechselforsch.=Horm. Me’tabolisme 41 (2009) 762–766, doi:http://dx.doi.org/10.1055/s-0029-1225629.
[95] O. Kose, T. Arabaci, A. Kara, H. Yemenoglu, E. Kermen, A. Kizildag, S. Gedikli, S.Ozkanlar, Effects of melatonin on oxidative stress index and alveolar boneloss in diabetic rats with periodontitis, J. Periodontol. 87 (2016) e82–90, doi:http://dx.doi.org/10.1902/jop.2016.150541.
[96] A. Slominski, D.J. Tobin, M.A. Zmijewski, J. Wortsman, R. Paus, Melatonin inthe skin: synthesis, metabolism and functions, Trends Endocrinol. Metab. 19(2008) 17–24, doi:http://dx.doi.org/10.1016/j.tem.2007.10.007.
[97] T.W. Fischer, A. Slominski, M.A. Zmijewski, R.J. Reiter, R. Paus, Melatonin as amajor skin protectant: from free radical scavenging to DNA damage repair,Exp. Dermatol. 17 (2008) 713–730, doi:http://dx.doi.org/10.1111/j.1600-0625.2008.00767.x.
[99] M.R. Namazi, G.O.H. Chee Leok, Vitiligo and diet: a theoretical molecularapproach with practical implications, Indian J. Dermatol. Venereol. Leprol. 75(2009) 116–118 http://www.ncbi.nlm.nih.gov/pubmed/19293496 (accessedAugust 20, 2016).
[100] B.N. Khandalavala, M.C. Nirmalraj, Rapid partial repigmentation of vitiligo ina young female adult with a gluten-free diet, Case Rep. Dermatol. 6 (2014)283–287, doi:http://dx.doi.org/10.1159/000370303.
[101] F. Miot, C. Dupuy, J. Dumont, B. Rousset, Chapter 2 Thyroid HormoneSynthesis And Secretion, MDText.com, Inc., 2000, 2017 http://www.ncbi.nlm.nih.gov/pubmed/25905405 (accessed August 20, 2016).
[102] T.S.S. Rao, M.R. Asha, B.N. Ramesh, K.S.J. Rao, Understanding nutrition,depression and mental illnesses, Indian J. Psychiatry 50 (2008) 77–82, doi:http://dx.doi.org/10.4103/0019-5545.42391.
[103] Z. Wang, J. Li, Z. Wang, L. Xue, Y. Zhang, Y. Chen, J. Su, Z. Li, L-tyrosine improvesneuroendocrine function in a mouse model of chronic stress, Neural Regen.Res. 7 (2012) 1413–1419, doi:http://dx.doi.org/10.3969/j.issn.1673-5374.2012.18.008.
[104] A. Slominski, M.A. Zmijewski, J. Pawelek, L-tyrosine and L-dihydroxyphenylalanine as hormone-like regulators of melanocytefunctions, Pigment Cell Melanoma Res. 25 (2012) 14–27, doi:http://dx.doi.org/10.1111/j.1755-148X.2011.00898.x.
[105] J.D. Fernstrom, M.H. Fernstrom, Tyrosine, phenylalanine, and catecholaminesynthesis and function in the brain, J. Nutr. 137 (2007) 1539S-1547S;discussion 1548S. http://www.ncbi.nlm.nih.gov/pubmed/17513421(accessed July 23, 2016).
[106] M.C. Reed, A. Lieb, H.F. Nijhout, The biological significance of substrateinhibition: a mechanism with diverse functions, Bioessays 32 (2010) 422–429, doi:http://dx.doi.org/10.1002/bies.200900167.
[107] G.M. Cooper, The Central Role of Enzymes as Biological Catalysts, (2000) .[108] R.L. Burton, S. Chen, X.L. Xu, G.A. Grant, A novel mechanism for substrate
inhibition in mycobacterium tuberculosis D-3-phosphoglyceratedehydrogenase, J. Biol. Chem. 282 (2007) 31517–31524, doi:http://dx.doi.org/10.1074/jbc.M704032200.
[109] S.L. Bulfer, E.M. Scott, L. Pillus, R.C. Trievel, Structural basis for L-lysinefeedback inhibition of homocitrate synthase, J. Biol. Chem. 285 (2010)10446–10453, doi:http://dx.doi.org/10.1074/jbc.M109.094383.
[110] C.A. Adebamowo, D. Spiegelman, C.S. Berkey, F.W. Danby, H.H. Rockett, G.A.Colditz, W.C. Willett, M.D. Holmes, Milk consumption and acne in teenagedboys, J. Am. Acad. Dermatol. 58 (2008) 787–793, doi:http://dx.doi.org/10.1016/j.jaad.2007.08.049.
[111] N. Kazakevich, M.N. Moody, J.M. Landau, L.H. Goldberg, Alcohol and skindisorders: with a focus on psoriasis, Skin Therapy Lett. 16 (2011) 5–6 http://www.ncbi.nlm.nih.gov/pubmed/21611681 (accessed August 20, 2016).
[112] D.D. Lynn, T. Umari, C.A. Dunnick, R.P. Dellavalle, The epidemiology of acnevulgaris in late adolescence, Adolesc. Health. Med. Ther. 7 (2016) 13–25, doi:http://dx.doi.org/10.2147/AHMT.S55832.
[113] M. Schlumpf, J. Reichrath, B. Lehmann, H. Sigmundsdottir, L. Feldmeyer, G.F.Hofbauer, W. Lichtensteiger, Fundamental questions to sun protection: acontinuous education symposium on vitamin D, immune system and sunprotection at the University of Zürich, Dermatoendocrinology 2 (2010) 19–25, doi:http://dx.doi.org/10.4161/derm.2.1.12016.
[114] D.W. Lachenmeier, Safety evaluation of topical applications of ethanol on theskin and inside the oral cavity, J. Occup. Med. Toxicol. 3 (2008) 26, doi:http://dx.doi.org/10.1186/1745-6673-3-26.
[115] S.N. McKenzie, P. Turton, K. Castle, S.M. Clark, M.R. Lansdown, K. Horgan,Alcohol hand abuse: a cross-sectional survey of skin complaints and usagepatterns at a large UK teaching hospital, JRSM Short Rep. 2 (2011) 68, doi:http://dx.doi.org/10.1258/shorts.2011.011034.
[117] M. Dudda, P. Godau, S. Al-Benna, T.A. Schildhauer, M. Gothner, Vitiligo andallergic complications from orthopaedic joint implants: the role of benzoylperoxide, Recent Pat. Inflamm. Allergy Drug Discov. 7 (2013) 176–182 http://www.ncbi.nlm.nih.gov/pubmed/23574546 (accessed August 20, 2016).
[118] S.A. Birlea, P.R. Fain, R.A. Spritz, A Romanian population isolate with highfrequency of vitiligo and associated autoimmune diseases, Arch. Dermatol.144 (2008) 310–316 http://www.ncbi.nlm.nih.gov/pubmed/18347286(accessed July 11, 2016).
[119] R.S. Balgir, Contribution of marital distance to community inbreeding,homozygosis, and reproductive wastage for recessively inherited geneticdisorders in madhya pradesh, India, Mediterr. J. Hematol. Infect. Dis. 5 (2013)e2013063, doi:http://dx.doi.org/10.4084/MJHID.2013.063.
[120] G.A. Molnár, S. Kun, E. Sélley, M. Kertész, L. Szélig, C. Csontos, K. Böddi, L.Bogár, A. Miseta, I. Wittmann, Role of tyrosine isomers in acute and chronicdiseases leading to oxidative stress – a review, Curr. Med. Chem. 23 (2016)667–685 http://www.ncbi.nlm.nih.gov/pubmed/26785996 (accessed July25, 2016).
[121] J.W. Shin, K.M. Nam, H.R. Choi, S.Y. Huh, S.W. Kim, S.W. Youn, C.H. Huh, K.C.Park, Erythrocyte malondialdehyde and glutathione levels in vitiligo patients,Ann. Dermatol. 22 (2010) 279–283, doi:http://dx.doi.org/10.5021/ad.2010.22.3.279.
[122] V. Rogosi�c, L. Boji�c, N. Puizina-Ivi�c, L. Vanjaka-Rogosi�c, M. Titli�c, D. Kovacevi�c,D. Duplanci�c, D. Mendes, D. Sapunar, Z. Dogas, Vitiligo and glaucoma – anassociation or a coincidence? A pilot study, Acta Dermatovenerol. Croat. 18(2010) 21–26 http://www.ncbi.nlm.nih.gov/pubmed/20361884 (accessedAugust 20, 2016).
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