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Chemical and instrumental approaches to treat hyperpigmentation.

Many modalities of treatment for acquired skin hyperpigmentation are available including chemical agents or physical therapies, but none are completely satisfactory. Depigmenting compounds should act selectively on hyperactivated melanocytes, without short- or long-term side-effects, and induce a permanent removal of undesired pigment. Since 1961 hydroquinone, a tyrosinase inhibitor, has been introduced and its therapeutic efficacy demonstrated, and other whitening agents specifically acting on tyrosinase by different mechanisms have been proposed. Compounds with depigmenting activity are now numerous and the classification of molecules, based on their mechanism of action, has become difficult. Systematic studies to assess both the efficacy and the safety of such molecules are necessary. Moreover, the evidence that bleaching compounds are fairly ineffective on dermal accumulation of melanin has prompted investigations on the effectiveness of physical therapies, such as lasers. This review which describes the different approaches to obtain depigmentation, suggests a classification of whitening molecules on the basis of the mechanism by which they interfere with melanogenesis, and confirms the necessity to apply standardized protocols to evaluate depigmenting treatments.

Animals↗

Hyperpigmentation due to topical calcipotriol and photochemotherapy in two psoriatic patients.

The vitamin D3 analogue calcipotriol (calcipotriene) is an effective topical treatment for psoriasis. In combination with other antipsoriatic agents, such as ultraviolet radiation, calcipotriol is reported to improve the overall efficacy of the treatment. Here we describe two patients treated with a combination treatment of calcipotriol and bath psoralens and ultraviolet A who developed hyperpigmentation at the lesional sites where calcipotriol ointment was applied.

Adult↗

Unusual hyperpigmentation developing in congenital reticular ichthyosiform erythroderma (ichthyosis variegata).

We present an unusual new clinical feature which developed in a patient with congenital reticular ichthyosiform erythroderma. This rare ichthyotic disorder is characterized by erythematous ichthyotic skin surrounding slowly enlarging areas of normal skin, and by a pathognomonic ultrastructural pattern, namely perinuclear deposits of a filamentous material in vacuolized keratinocytes. At the age of 18 years, a 23-year-old woman developed several irregular hyperpigmented macules on her limbs, which were almost black in colour. These lesions have not been observed in the other patients affected by the disease nor, to our knowledge, in other ichthyotic disorders. Electron microscopy and immunohistochemistry demonstrated that the lesions were strictly related to the ichthyotic skin and that their dark colour was especially due to melanosome accumulation in activated dendritic melanocytes. An unusual postinflammatory hyperpigmentation, in which the lack of pigment deposition in the keratinocytes is due to a transfer defect in pathological cells, is hypothesized. A characteristic hyperplastic stimulation of the epidermis is also taken into consideration to explain the lack of a similar picture in other erythrodermic ichthyotic disorders with a continuous inflammatory process.

Adult↗

The mechanism of hyperpigmentation in seborrhoeic keratosis involves the high expression of endothelin-converting enzyme-1alpha and TNF-alpha, which stimulate secretion of endothelin 1.

BACKGROUND: Seborrhoeic keratosis (SK) is a benign epidermal tumour with increased pigmentation. We have recently demonstrated that increased secretion of endothelin (ET)-1, a strong keratinocyte-derived mitogen and melanogen for human melanocytes, is intrinsically involved in the hyperpigmentation mechanism of SK. OBJECTIVES: To examine whether the increased ET secretion results from cytokines that induce ET production and/or from differences in the processing of ET that lead to its final active, secreted form. METHODS: We used immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR) to determine whether ET-inducing enzymes and/or cytokines are also highly expressed in SK. RESULTS: RT-PCR of mRNAs encoding interleukin (IL)-1alpha, tumour necrosis factor (TNF)-alpha and endothelin-converting enzyme (ECE)-1alpha demonstrated that there is an increased expression of TNF-alpha and ECE-1alpha mRNAs in SK, whereas the IL-1alpha transcript is rather downregulated in SK compared with that in perilesional normal epidermis. In parallel, immunohistochemical analysis of SK revealed marked immunostaining for TNF-alpha in basaloid cells at lower levels of the epidermis and in basal cells, and for ECE-1alpha in most basaloid and basal cells in comparison with their weak staining throughout the epidermis in perilesional normal controls. In contrast, immunostaining for IL-1alpha was almost negative in SK relative to distinctive staining throughout the epidermis in the perilesional normal controls. CONCLUSIONS: These findings suggest that the increased secretion of ET-1 leading to enhanced pigmentation in SK results from the co-ordinated increased expression of TNF-alpha and ECE-1alpha.

Cell Culture Techniques↗

Aloesin inhibits hyperpigmentation induced by UV radiation.

Skin hyperpigmentation is caused by the overproduction of melanin pigment, which is synthesized by the action of tyrosinase. We recently reported that aloesin inhibits tyrosinase activity. The present study was undertaken to test the inhibitory effect of aloesin on pigmentation in human skin after UV radiation. Experimental subjects were UV-irradiated (210 mJ) on the inner forearm. UV-irradiated regions were assigned to four groups: vehicle control, aloesin treated, arbutin treated, and aloesin and arbutin treated. Aloesin and/or arbutin were administered four times a day for 15 days. Aloesin treatment suppressed pigmentation by 34%, arbutin by 43.5%, and the cotreatment by 63.3% compared with the control (n = 15; P < 0.05). Moreover, aloesin treatment showed pigmentation suppression in a dose-dependent manner (n = 7; P < 0.05). These results raise the possibility that aloesin may be used as an agent that inhibits melanin formation induced by UV radiation.

Adult↗

Optimal treatments for hyperpigmentation.

The current treatment of hyperpigmentation relies on multiple modalities to achieve satisfactory cosmetic results. Patients are savvy consumers who often present to physicians asking about the latest treatments and breakthroughs. By combining topical bleaching agents, chemical peels, laser therapy, and adequate photo-protection, many pigmentary disorders can be successfully treated. A review of recent trials and new technologies will be discussed.

Administration, Topical↗

Minocycline hyperpigmentation isolated to the subcutaneous fat.

We present a 15-year-old girl with bilateral lower extremity discoloration of one-year duration while taking minocycline for acne vulgaris. The clinical characteristics best supported type II minocycline hyperpigmentation, but the histology revealed that the pigmentation was solely limited to the subcutaneous adipose tissue, completely sparing the dermis. Special stain for iron was negative. This is the first case to our knowledge with pigment exclusively located in the subcutaneous fat and with the unusual finding of a negative stain for iron.

Acne Vulgaris↗

A new type of minocycline-induced cutaneous hyperpigmentation.

Pigmentary disorders are recognized adverse effects of the semi-synthetic tetracycline derivative antibiotic, minocycline. Three distinct types of minocycline-induced cutaneous pigmentation have been described. Type I, blue-black pigmentation confined to sites of scarring or inflammation on the face; Type II, blue-grey circumscribed pigmentation of normal skin of the lower legs and forearms; and Type III, diffuse muddy brown pigmentation of normal skin accentuated in sun-exposed areas. We report two patients with acne vulgaris with a fourth type of minocycline-induced cutaneous pigmentation. They presented with circumscribed blue-grey pigmentation within acne scars confined to the back. Histology showed pigment within dendritic cells, and extracellularly throughout the dermis. Histochemistry identified a calcium containing melanin-like substance. Iron was absent. Immunohistochemistry confirmed some pigment-containing cells to be macrophages. Electron microscopy demonstrated electron-dense granules, free and membrane-bound, within macrophages and fibroblast-like cells. Energy-dispersive X-ray analysis confirmed the presence of calcium. Iron was absent. This fourth type of cutaneous minocycline hyperpigmentation may be a variant of Type I, but based on clinical, pathological and microanalytical differences, appears to be a new entity. The pigment may be a drug metabolite-protein complex chelated with calcium, or an insoluble minocycline-melanin complex. We propose a classification of cutaneous minocycline pigmentation based on clinico-pathological criteria.

Acne Vulgaris↗

Hyperkeratosis-hyperpigmentation syndrome: a confirmative case.

A 22-year-old female showing hyperpigmented spots and mild palmoplantar hyperkeratosis as leading features is presented. The diagnosis of Hyperkeratosis-hyperpigmentation syndrome, previously described by our group as an autosomal dominant trait, was unmistakable, thus permitting the corroboration of this genodermatosis.

Adult↗

Tongue and skin hyperpigmentation during PEG-interferon-alpha/ribavirin therapy in dark-skinned non-Caucasian patients with chronic hepatitis C.

Various skin disorders may occur during antiviral therapy with interferon (IFN) and ribavirin (RBV) for chronic hepatitis C. This article describes to our knowledge the first report of lingual hyperpigmentation during pegylated (PEG)-IFN/RBV combination therapy in five dark-skinned hepatitis C virus (HCV) patients. Lingual pigmentation during antiviral therapy was not associated with age, gender, HCV genotype, doses of RBV, or duration of the treatment or treatment outcome. Since IFN increases the expression of alpha-melanocyte-stimulating hormone (MSH) surface receptors, the use of PEG-IFN having a longer plasma half-life may even increase incidence for such cutaneous side effects particularly in dark-skinned HCV patients.

Adult↗

The role of endothelin-1 in epidermal hyperpigmentation and signaling mechanisms of mitogenesis and melanogenesis.

The paracrine linkage of endothelins (ET) between keratinocytes and melanocytes suggested that ETs are intrinsic mediators for human melanocytes in UVB-induced pigmentation. In this study, the role of ET-1 in the epidermal hyperpigmentation was investigated in vivo and in vitro. The addition of 10 nM ET-1 induced a H-7 (10 microM) suppressible-increase in tyrosinase activity in cultured human melanocytes and was accompanied by elevated levels of tyrosinase and tyrosinase-related protein-1 mRNA expression as shown by Northern blotting. Analysis of signaling mechanisms leading to tyrosinase activation demonstrated the involvements of quick translocation of PKC, the H-7 (10 microM) suppressible-phosphorylation of the threonine residue of several proteins, and highly elevated level of cyclic AMP (4-fold over control). Reverse transcription polymerase chain reaction (RT-PCR) of RNA isolated from the epidermis of human skin exposed to UVB revealed that UVB irradiation with a dose of 2 MED caused a significant increase in the expressions of ET-1, IL-1 alpha, and tyrosinase mRNA signals 5 days after irradiation. The involvement of ET-1 in UVB-pigmentation was also corroborated by the experiments that the extracts of M. Chamomilla, which can act as an antagonist for ET-receptor binding-mediated signaling but has no inhibitory effect on tyrosinase activity in culture, had a significant inhibitory effect on UVB-induced pigmentation in vivo when daily applied immediately after UVB exposure to human skin. These findings suggest that ET-1 is an important mediator in the epidermis for UVB-induced pigmentation in vivo.

Cell Division↗

Topical methimazole as a new treatment for postinflammatory hyperpigmentation: report of the first case.

We have previously shown that the peroxidase inhibitor methimazole (1-methyl-2-mercapto imidazole; MMI) is a noncytotoxic inhibitor of melanin production in cultured B16 melanocytes. It was further demonstrated that the topical application of 5% MMI on brown guinea pig skin for 6 weeks causes a significant reduction in the amount of epidermal melanin, resulting in visually recognizable cutaneous depigmentation. Herein, we report a 27-year-old male with postinflammatory hyperpigmentation (due to acid burn), successfully treated with topical MMI as a new skin depigmenting agent. Topical 5% MMI caused a moderate to marked improvement of the hyperpigmented lesions within 6 weeks of once-daily application. Topical MMI was well tolerated by the patient and did not affect the level of serum thyroid hormones (free thyroxin, free triiodothyronine and the thyroid-stimulating hormone). Unlike most known depigmenting agents, such as hydroquinone and kojic acid, MMI is a noncytotoxic, nonmutagenic compound, and it is possible that MMI could serve as a novel agent for the treatment of hyperpigmentary disorders in human.

Administration, Cutaneous↗

Cobalamin deficiency presenting with cutaneous hyperpigmentation: a report of two siblings.

The authors report on 2 children with pernicious anemia, sisters, who presented with hypermelanosis as one of the clinical manifestations. The hypermelanosis disappeared with adequate treatment of vitamin B12 deficiency. Vitamin B12 deficiency should be considered in the differential diagnosis of a child presenting with hyperpigmentation and macrocytic red cell indices.

Child, Preschool↗

Hyperpigmentation of the distal phalanx in healthy Caucasian neonates.

Transient alterations in pigmentation are frequently observed in black neonates, but to our knowledge, have not previously been reported in Caucasian infants. In 54 Caucasian newborns, we found at least mild periungual hyperpigmentation similar to the variation in coloration in the periungual region of many black newborns. This pigmentation should be added to the transient benign dermatoses of Caucasian infants.

Age Distribution↗

A new type of tyrosinase inhibitors from natural products as potential treatments for hyperpigmentation.

Selected flavonoids were evaluated for their effects on melanin biosynthesis by using mushroom-tyrosinase assay. Out of 27 tested flavonoids, only six showed a potential inhibitory activity on melanin biosynthesis. Flavonoids containing an alpha-keto group showed to be the active compounds in this assay. This may be explained in terms of similarity between the dihydroxyphenyl group in L-DOPA and the alpha-ketol group in flavonoids. The results of this study revealed a new type of tyrosinase inhibitor from natural origin. These compounds will be further examined for their application for treatment of hyperpigmentation problems e.g. melasma and ephelides.

Anthocyanins↗

HPV 29-associated spotted hyperpigmentation of the face.

A healthy immunocompetent 40-year-old man presented with spotted hyperpigmentation of the face. Skin-biopsies taken from these lesions revealed slight acanthosis of the epidermis with vacuolization within the keratinocytes in the upper malpighian layer similar to HPV-induced cytopathic viral effects. Polymerase chain reaction analysis and subsequent direct DNA sequencing could clearly demonstrate the presence of HPV 29 DNA in the hyperpigmented macules. To our knowledge, this is the first report of facial hyperpigmented lesions induced by HPV 29.

Adult↗