Current concepts in melasma - A review article

Role of genetic factors

Evidence from various epidemiological studies have shown strong correlation between family history and racial factors in the pathogenesis of melasma.

Although there is a wide variation in the rate of positive family history in various studies, they still show a strong correlation. Positive family history rate as high as 61% has been reported.^[2] High incidence of positive family history has also been reported in Indian studies.^[3]

There is a high incidence of melasma in Latin Americans and Hispanics and in Asians with Fitzpatrick skin types III–V.^[4,5]

The patients with melasma were found to have downregulation of the H19 gene in both hyperpigmented and normally pigmented skin. This leads to downstream effects which lead to stimulation of melanogenesis and increase in transfer of melanin to keratinocytes.^[6]

Other genes concerned are those involved in melanin biosynthesis, especially the genes that encode tyrosinase (TYR), tyrosinase-related proteins TRP1 and TRP2, and microphthalmia-associated transcription factor (MITF), which is responsible for transcriptional regulation. There is upregulation of genes encoding TYR, MITF, and TRP1 in melasma skin.

Wnt pathway modulation genes, which have role in proliferation of melanocyte stem cells, genes involved in prostaglandin (PG) synthesis and genes in fatty acid metabolism are also implicated in melasma.^[7]

There is a reduced expression of Wnt inhibitory factor-1 (WIF-1) in the hyperpigmented skin of melasma patients irrespective of ultraviolet irradiation. WIF-1 downregulation occurs in both epidermal keratinocytes and in dermal fibroblasts but not in melanocytes. It mediates its effect in melasma by stimulation of melanogenesis and melanosome transfer.^[8]

Ultraviolet radiation (UVR) induces downregulation of genes involved in lipid metabolism such as peroxisome proliferator-activated receptor alpha (PPAR), arachidonate 15-lipoxygenase, and PPAR gamma coactivator-1 alpha.^[9] The altered lipid metabolism in the lesional skin adversely affects the barrier function in melasma.

Role of sun exposure

Exposure to sunlight is undoubtedly the most important factor and both UVR and visible light stimulate melanogenesis. The mechanism involved is as follows:

1. Direct effect on melanocytes – By stimulating the formation of endogenous 1,2- diacylglycerol formation from melanocytes.^[10] Nitric oxide production from keratinocytes is also stimulated which has got a paracrine effect on melanocytes and this leads to an increase in amount of both tyrosinase and tyrosinase-related protein 1.^[11]

2. Indirect effect on keratinocytes which release melanogenic factors – These melanogenic factors include basic fibroblast growth factor, nerve growth factor, endothelin 1, and Proopiomelanocortin-derived peptides such as melanocyte-stimulating hormone and adrenocorticotrophic hormone.^[12]

3. UV light induces production of reactive oxygen species (ROS) by activating inducible nitric oxide synthase which stimulates melanogenesis.^[13] The level of oxidative stress is higher in patients with melasma.^[14]

4. Visible light is also able to induce pigmentation and it has been recognized that the visible light-induced pigmentation is more intense and stable compared to UV-A.^[15] This highlights the importance of adding a physical sunscreen for better control of melasma. v. UV and visible light-induced dermal inflammation lead to upregulation of stem cell factor (SCF) production by dermal fibroblast, which is a ligand for tyrosine kinase receptor (c-kit). This increased expression of SCF in dermis and c-kit in epidermis lead to stimulation of melanogenesis.^[16]

5. There is UV-induced synthesis of PG and upregulation of cyclooxygenase 2 which stimulates melanogenesis.^[17] The emerging use of PG analogs in the treatment of vitiligo favors this theory.

Role of hormones

Role of vascular factors

UVR can induce secretion of vascular endothelial growth factor (VEGF) from keratinocytes. Melanocytes express functional receptors for VEGF and it enhances melanogenesis.^[26] This is exemplified by the presence of prominent telangiectasia visualized on dermoscopy on lesional skin in melasma and also the therapeutic efficacy of tranexamic acid and vascular lasers in the treatment of melasma.

Role of neural factor

The presence of melasma along the distribution of trigeminal nerves suggests the role of neural involvement in the pathogenesis. Higher levels of neural endopeptidase in melasma lesions were detected which shows that neuroactive molecules, including nerve growth factor, may play a significant role in the pathogenesis of melasma.^[27]

Role of drugs

Phenytoin has been implicated in the development of melasma like pigmentation which acts by directly causing dispersion of melanin granules and by inducing pigmentation of basal epidermis. This pigmentation is reversible following withdrawal of the drug.^[28]

Other factors

Role of microRNA (miRNA)

miRNAs are a family of small, 20–24 nucleotide, endogenously expressed non-coding RNAs which have a role in post-transcriptional regulation of gene expression either by blocking translation or by promoting transcript degradation.^[35]

miRNA-125b is identified as a regulator of steady-state melanogenesis in the absence of external stimuli.^[36]

miRNA has an important role in melanogenesis and melanosome transfer. Expression of an H19 RNA-derived miRNA, miR-675, is reduced in the hyperpigmented skin of melasma patients. Overexpression of miR-675 decreases the expression of tyrosinase, TRP-1, and TRP-2, whereas its knockdown increases their expression.^[37]