The correlation between melanin & skin color as a precursory understanding of phenotype plasticity, disease & treatment.

Melanin, a polymer that is produced by melanocytes, is known to give skin and hair its pigmentation. It is broken up into two different types: pheomelanin and eumelanin. Pheomelanin gives off a red or yellow pigmentation and eumelanin gives off a brown or black pigmentation. Depending on a person’s location and UV exposure, they may have one of the two types of melanin. For example, people who live closer to the equator are more likely to develop eumelanin because they are in a direct relationship with the sun compared to people who live closer to the poles who would have pheomelanin. Although over-exposure to UV light can be harmful such as causing melanoma which is a mutation in the DNA sequence, it can also provide benefits by stimulating the production of vitamin D which regulates calcium and promotes bone growth. Vitamin D can also help in treating autoimmune disorders such as vitiligo and healing burns.

Vitiligo

This autoimmune skin disorder can be described as pigmented macules of different sizes spread out across the surface of the skin. Vitiligo is caused by melanocytes being destroyed at the cutaneous layer. Even though vitiligo affects a small percentage of the population, it can affect different types of people independent of the skin tone. It not only has a physical effect on the skin, but also a psychological effect on the individual from rejection in society. A systematic review found that topical vitamin D analogues may be able to boost pigmentation within the skin. The active form of vitamin D (1,25-dihydroxyvitamin D3) has a wide range of functions from regulating calcium, to bone growth, to preventing or treating certain diseases such as osteoporosis, psoriasis, and vitiligo. There were some studies that showed how topical vitamin D3 analogues such as calcipotriol and tacalcitol used with or without ultraviolet light or corticosteroids may enhance pigmentation in patients with vitiligo. Furthermore, numerous studies demonstrated that the vitamin D3 analogues used in combination with PUVA, NBUVB, or an excimer laser are effective and safe in treatment compared to placebo with PUVA. This is because calcipotriol works on melanocytes, inflammation mechanisms, and other immunomodulatory systems because it can activate melanin production.

Burn Healing

Burns can damage the healthy layer of skin. Depending on how severe the burn is, it can also disrupt the production of vitamin D permanently. Vitamin D is proven to enhance wound healing and improve the immune system which could protect burn patients from serious infection. Because of this reason, vitamin D supplementation has become a significant source for these specific types of patients. When a patient experiences a severe burn, their vitamin D levels can drop. This is dependent on the burned BSA. A study was conducted to analyze the correlation between low vitamin D levels in the body with healing time in burn victims. It was found that patients were more likely to not only have longer healing time, but also increased hospitalization time. A different study that was conducted by Oxford University, demonstrated that patients who did not have a vitamin D deficiency were more likely to have a lower burned BSA which could contribute to faster healing time. The lack of vitamin D in certain patients was due to reduced UV exposure which led to longer hospitalization and prolonged healing time. In order to decrease hospitalization time, intensive rehab centers for burn patients need to consider early initiation of vitamin D supplementation.

References

AlGhamdi K, Kumar A, Moussa N. (2013). The role of vitamin D in melanogenesis with an emphasis on vitiligo. Indian J Dermatol Venereol Leprol. 79(6):750-8. doi: 10.4103/0378-6323.120720. PMID: 24177606.

Cho, Y. S., Seo, C. H., Joo, S. Y., & Ohn, S. H. (2020). The association between vitamin D levels and burn factors in different burn types. Burns & trauma, 8, tkaa018. https://doi.org/10.1093/burnst/tkaa018

As mentioned in the videos melanin is an important protectant produced by the body and produce pigment. As it was theorized that we all came from Africa, a location so close to the equator, most of our ancestors were always exposed to the sun. Therefore their bodies produced more melanin as a way of protecting their skins from the harmful rays of the sun. Another way of seeing this is that the melanin produced by melanocytes acts as a shield to protect us from too much of the sun rays, but this doesn’t mean none of the rays gets absorbed. Some of the sun’s rays are important to be absorbed so that our bodies are able to use the vitamin d it gives to help strengthen our bones. Prolonged exposure to sun without proper protection can also cause other skin issues and more dangerous diseases such as cancer. Other skin condition can be due to photoaging or even mutation of melanocytes. As our ancestors migrated away from the equator they adapted to the environment and their bodies began producing less melanin in order to absorb more sunlight and to make sure the body can produce vitamin d and strengthen the bones.

It is important for those with “fair” skin to be more protected from the sun as they are more susceptible to deadly diseases such as cancer since their melanin shield is not as strong as that of someone of color. A way to protect the skin is the consistent use of sunscreen/sunblock. So then the question poses, if people of color have more protection from the sun due to an increased production of melanin, does this mean they shouldn’t be wearing sunscreen as an added layer of defense? Not many studies have been conducted regarding this specifically, but it can be said that no matter what the color of your skin is sunscreen is a must in our daily skincare routine. Just because you are more protected doesn’t mean that the sun’s rays won’t affect you at all.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4853009/

Vitamin D Use:

The body needs Vitamin D to absorb calcium, which is crucial in maintaining bone health. Most Vitamin D people get is from the sun. The body uses the sun’s light on the skin to produce Vitamin D. Without vitamin D, patients are more likely to have weak or brittle bones, that can cause them to easily break. This also results in weaker muscles, that induces falls and breakage. Those at highest risk for Vitamin D deficiency are patients that spend most of their time indoors or live in cooler climates with a lack of UVB radiation. Patients with certain disease states can also be at increased risk for vitamin D deficiency such as patients with Chronic Kidney Disease or End Stage Renal Disease, Cystic Fibrosis and Osteoporosis because of difficulties absorbing the Vitamin D in the body. It is recommended for patients with this deficiency to take supplements in conjunction with foods and drinks that have a lot of vitamin D like milk, orange juice, cod liver oil, or salmon.

Cystic Fibrosis:

CF patients are known to have Vitamin D deficiency due to various causes including pancreatic exocrine insufficiency, lack of vitamin D metabolism and lack of exercise and activity outdoors. Higher doses of vitamin D are necessary in CF patients because they are known to have fat malabsorption. Studies have shown that higher vitamin D status is related to better lung function in these patients so Vitamin D supplementation when low is crucial. The exact mechanism by which the use of Vitamin D is associated with better outcomes in CF patients is not yet determined but Vitamin D supplementation is something that should be considered in these patients.

Chronic Kidney Disease:

Chronic Kidney Disease (CKD) and End Stage Renal Disease (ESRD) are known to cause bone abnormalities and mineral metabolism abnormalities, known as CKD bone mineral disorder. This can lead to conditions like hyperparathyroidism and mixed uremic osteodystrophy. These conditions are the lead causes of reduced concentrations of 1.25- dihydroxy Vitamin D and absorption of calcium. Treatment with activated Vitamin D, or calcitriol, is recommended for these patients since they are unable to properly metabolize the inactive form.

Fracture Prevention:

Older persons are at risk of developing fractures due to weaker bones as age increases. Studies done to estimate efficacy of Vitamin D supplementation in preventing hip and nonvertebral fracture in the elderly revealed that Vitamin D supplementation between 700 to 800 units a day appears to reduce hip and nonvertebral fracture risk in elderly patients that have been institutionalized.

Osteoporosis:

The elderly population are at the highest risk for osteoporosis. It is more likely to affect older elderly women post menopause as they have less estrogen as they age. Vitamin D is used in conjunction with calcium with prevention and treatment of osteoporosis in addition to lifestyle modifications including tobacco use and alcohol use cessation, regular weight bearing exercise recommending 800-1000 units of vitamin D for persons 50 years and older (recommendation from the National Osteoporosis Foundation).

References:

Chesdachai S, Tangpricha V. Treatment of vitamin D deficiency in cystic fibrosis. J Steroid Biochem Mol Biol. 2016 Nov;164:36-39. doi: 10.1016/j.jsbmb.2015.09.013. Epub 2015 Sep 10. PMID: 26365559; PMCID: PMC4786457.

Zand L, Kumar R. The Use of Vitamin D Metabolites and Analogues in the Treatment of Chronic Kidney Disease. Endocrinol Metab Clin North Am. 2017 Dec;46(4):983-1007. doi: 10.1016/j.ecl.2017.07.008. Epub 2017 Sep 29. PMID: 29080646; PMCID: PMC5977979.

Bischoff-Ferrari HA, Willett WC, Wong JB, Giovannucci E, Dietrich T, Dawson-Hughes B. Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials. JAMA. 2005 May 11;293(18):2257-64. doi: 10.1001/jama.293.18.2257. PMID: 15886381.

Melanin can offer our skin more protection from damaging UVA and UVB rays that are the leading causes of skin melanomas including basal cell carcinoma, squamous cell carcinoma and malignant melanoma. There are two classes of melanin including eumelanin that Is the main type found in brown/black pigments, and pheomelanin which is found in yellow/red/brown pigments. One way that melanin protects the skin from UV rays is by absorbing and redistributing light energy from the rays, and by shielding our genetic material stored in nuclei from the rays. Individuals with higher amount of melanin in their skin are found to have melanosomes that are more resistant to cellular degradation compared to individuals with a lower amount of melanin produced. Additionally, melanin has and SPF of around 1.5-2, and can even go as high as 4, doubling the amount of protection the skin has from the destructive sun rays. There is additional evidence that melanin can be toxic to cells grown in culture dishes after UV exposure. It can produce a reactive oxygen compound that can break a single DNA strand, leading to mutations in the skin cells. This contradicting evidence makes it difficult to determine whether it actually impacts the development or protection of cancer.

Vitamin D is a fat-soluble vitamin that has many benefits in outcomes when dealing with skin melanomas. Melanoma patients often avoid sunlight sue to their condition, and in most cases are found to have a higher risk of becoming vitamin D deficient. Therefore, vitamin D supplementation is an important part when regulating these levels in the blood in melanoma patients. Even though the mechanism id unknown, research has proven that vitamin D deficiency is associated with poorer outcomes in melanoma, while a higher level of Vitamin D in the blood is linked to smaller tumors and better outcomes. VDR protein found in each cell, indicates its gene activity and aggressiveness of the tumor. Low levels of VDR gene expression occurred in tumors with higher growth rates, and reduced VDR was linked to the Wnt/B catenin pathway, which influences cell growth. Even though vitamin D wont treat cancer levels on its own , regulated levels of vitamin D in the blood can help suppress this pathway with the help of immunotherapy. Low levels of Vitamin D were also linked to the inhibition of genes that regulate cancer-fighting immune responses.

Vitamin D deficiency has also been found with people who have psoriasis because it may impair the body’s ability to keep skin healthy. People with lower amount of vitamin D levels were linked to having increased flare ups specifically with chronic plaque psoriasis compared to those with sufficient levels of vitamin D. Vitamin D can also help strengthen the immune system, and since psoriasis is an autoimmune disease, regulated levels of vitamin D can drastically help treat the condition. Lastly patients with psoriasis have quicker rate of which new cells grow and accumulate on the surface of the skin which leads to the development of plaque, and vitamin D can help slow the growth of new cells.

Publishing, H. (n.d.). Psoriasis and vitamin D deficiency. Retrieved October 20, 2020, from https://www.health.harvard.edu/diseases-and-conditions/psoriasis-and-vitamin-d-deficiency

Slominski, R. M., Zmijewski, M. A., & Slominski, A. T. (2015). The role of melanin pigment in melanoma.Experimental dermatology,24(4), 258–259. https://doi.org/10.1111/exd.12618

Bavencio

Bavencio also known as avelumab is a fully human monoclonal antibody developed by Merck KGaA and Pfizer. It is an antibody that binds to programmed death ligand 1 (PD-L1) on tumor cells and prevents B7.1 from binding to the ligand. When B7.1 is able to bind to PD-L1 it down regulates anti-tumor t-cell function. By preventing these proteins from binding together we are able to restore normal antitumor t-cell function. Avelumab is FDA approved for the treatment of metastatic Merkel cell carcinoma (MCC) in adults and children ≥12 years of age. It is given as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. In the JAVELIN Merkel 200 study, 88 patients were treated with avelumab after having received previous chemotherapy. The results showed that there were 29 objective responses which included 10 complete responses. The two year overall survival rate was 36%. Adverse events reported with this medication include infusion-related reaction, fatigue, peripheral edema, hypertension, etc. Premedication with an antihistamine and acetaminophen is usually given prior to the first 4 infusions to prevent infusion-related reactions.

https://www.emdserono.com/us-en/pi/bavencio-pi.pdf

http://online.lexi.com.jerome.stjohns.edu:81/lco/action/doc/retrieve/docid/patch_f/6449706?cesid=8dOUTohcn3s&searchUrl=%2Flco%2Faction%2Fsearch%3Fq%3DBavencio%26t%3Dname%26va%3DBavencio#adr

https://www.uptodate.com/contents/staging-and-treatment-of-merkel-cell-carcinoma?search=Bavencio&source=search_result&selectedTitle=2~22&usage_type=default&display_rank=1#H1486586095

https://www.ncbi.nlm.nih.gov/pubmed?term=27592805

https://www.ncbi.nlm.nih.gov/pubmed?term=29347993

Aldara

Aldara also known as imiquimod is a topical immune response modifier approved for the treatment of superficial basal cell carcinoma (BCC). Imiquimod is a toll like receptor 7 agonist (TLR-7) and promotes the release of cytokines and other inflammatory markers triggering an immune response. The use of imiquimod is reserved for cases that are located in low risk areas where recurrence is unlikely and in scenarios where patients prefer not having surgery. The formulation used to treat BCC comes available as a 5% cream and is only applied to tumors with a diameter of 2 cm or less. It is applied once daily before bedtime 5 days per week for a total of 6 weeks and should be left on skin for about 8 hours before removing with soap and water. The most commonly reported adverse events are itching, redness, soreness, bleeding, and/or pain within the treated area. There have been a few studies that have assessed the efficacy and safety of Aldara for the treatment of superficial BCC. In two studies, 724 patients were treated with imiquimod 5% cream and placebo for 6 weeks. At week 12, the results showed that patients receiving imiquimod for five and seven day treatment (per week) had an 82 and 79 percent histologic clearance rate. In another trial the compared treatment with surgical excision and imiquimod showed that the clinical cure rates from surgical excision and imiquimod were 98 and 85 percent respectively. Aldara is effective in treating superficial BCC however, there are other options that yield a higher success rate.

https://www.ncbi.nlm.nih.gov/pubmed?term=15097956

https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020723s022lbl.pdf

http://online.lexi.com.jerome.stjohns.edu:81/lco/action/doc/retrieve/docid/patch_f/7077?cesid=5y5Faw8F2Oe&searchUrl=%2Flco%2Faction%2Fsearch%3Fq%3Daldara%26t%3Dname%26va%3Daldara#pha

https://www.ncbi.nlm.nih.gov/pubmed?term=27932240

Eucrisa

Eucrisa also known as crisaborole is a boron-based topical phosphodiesterase 4 (PDE4) inhibitor approved by the FDA for the treatment of mild to moderate atopic dermatitis (eczema) in adults and children 3 months and older. The exact mechanism in which Eucrisa helps to treat atopic dermatitis is not completely understood. This medication is available as a 2% ointment and it is applied to affected areas twice daily. Two phase 3 trials were conducted to evaluate the safety and efficacy of this medication (AD-301 and AD-302). Both trials involved treatment for 28 days with the primary outcome being a measure in the investigator's static global assessment (ISGA) score of a 0 or 1 and a 2 level improvement from baseline. In both trials, patients receiving treatment with Eucrisa saw a higher rate of success as compared to the control group (32.8% vs. 25.4% and 31.4% vs. 18%). Overall, there was an improvement of symptoms with adverse events only occurring in 4.4% of patients. Better trials that compare Eucrisa to other treatments are needed to determine its therapeutic benefit.

https://www.pfizermedicalinformation.ca/en-ca/eucrisa/action-and-clinical-pharmacology#

https://clinicaltrials.gov/ct2/show/NCT03250663

https://clinicaltrials.gov/ct2/show/NCT03356977

Efudex

Efudex also known as fluorouracil (5-FU) is a topical cream used to treat overgrowths on the skin and in some cases it can be used to treat superficial basal cell carcinoma. Fluorouracil is a pyrimidine antimetabolite that interferes with DNA synthesis. Pyrimidine is a compound that is found in DNA and RNA. 5-FU inhibits the production of thymidine by targeting a key enzyme known as thymidylate synthase. As a result of this, DNA synthesis and cell proliferation is halted and cell death follows. While topical fluorouracil is available in a number of strengths, the 5% cream or solution is used to treat carcinoma. It is applied to affected lesions twice daily for 3 to 6 weeks or up to 10 to 12 weeks. The most frequently observed side effects are burning, dry skin, swelling and redness. Evidence supporting the use of topical fluorouracil is limited and there is a concern that basal cell carcinomas may occur with use. Topical fluorouracil is considered first line therapy in the treatment of actinic keratosis and is usually combined with topical corticosteroids to reduce inflammation associated with 5-FU.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6244944/

https://www.uptodate.com/contents/treatment-of-actinic-keratosis#H745769568

https://www.uptodate.com/contents/treatment-and-prognosis-of-low-risk-cutaneous-squamous-cell-carcinoma

Atopic Dermatitis (AD) also known as eczema is a condition in which the skin becomes red and itchy. The exact cause is unknown but it is believed to be the result of an immune response to external triggers that precipitates inflammation. Research has showed that patients with atopic dermatitis lack filaggrin, a protein responsible for building a skin barrier to keep moisture in and prevent bacteria and virus from entering. There has also been a genetic link in which the chances of having atopic dermatitis increases by 50% if a parent had the same condition or had asthma or hay fever. While there is no cure for atopic dermatitis, treatment with topical corticosteroids are usually considered first line therapy and preferred over other drug classes. Another class of medication used to treat AD is called calcineurin inhibitors (tacrolimus, pimecrolimus) and they work by suppressing T-cell activation to prevent an immune response. In a review of 20 studies, it was concluded that topical 0.1% tacrolimus was better than low-potency corticosteroids on the face and neck areas and moderate-potency corticosteroids on the trunk and extremities. Patients should be aware of potential adverse effects associated with these medication including stinging and burning. Topical calcineurin inhibitors offer another alternative option to treat AD and in some cases can be used with topical corticosteroids.

https://www.jaad.org/article/S0190-9622(14)01257-2/fulltext

https://www.jwatch.org/pa200505060000005/2005/05/06/black-box-warning-tacrolimus-and-pimecrolimus

https://www.cochrane.org/CD009864/SKIN_topical-tacrolimus-atopic-dermatitis

Use of Vitamin D in Treating Certain Diseases.

Photoprotection

In vitro studies, researchers have found that vitamin D3 exhibits photo-protective effects when topically applied to the skin before or immediately following irradiation. "Documented effects on skin cells include decreased DNA damage, reduced apoptosis, increased cell survival, and decreased erythema". The mechanisms for such effects are not known, but one mouse study found that this vitamin induced expression of metallothionein (a protein that protects against free radicals and oxidative damage).

Wound healing

Since vitamin D3 regulates the expression of cathelicidin(antimicrobial protein), the possibility of wound healing and tissue repair with this agent is likely. One human study found that cathelicidin expression is upregulated during the early stages of normal wound healing. Other studies have shown that cathelicidin modifies inflammation in the skin. The active form of vitamin D has been shown to upregulate cathelicidin expression in cultured keratinocytes. However, more research is necessary to confirm the role of vitamin D in wound healing.

Psoriasis

Calcipotriol, a vitamin D3 analog, is a first-line topical agent for the treatment of plaque psoriasis and moderately severe scalp psoriasis. Multiple randomized trials have shown calcipotriol to be safe and efficacious for patients with mild plaque psoriasis and not inferior to most corticosteroids with respect to efficacy.

Mostafa, W. Z., & Hegazy, R. A. (2015). Vitamin D and the skin: Focus on a complex relationship: A review.Journal of advanced research,6(6), 793–804. https://doi.org/10.1016/j.jare.2014.01.011

Ashcroft DM, Po AL, Williams HC, Griffiths CE. Systematic review of comparative efficacy and tolerability of calcipotriol in treating chronic plaque psoriasis. BMJ 2000;320(7240):963-7.

The Protective Role of Melanin Against UV Damage in Human Skin

As mentioned in the videos, skin cells called melanocytes have a light-receptor molecule called rhodopsin that fluoresces as soon as it detects ultra-violet A light This receptor also triggers a vital step in melanin production. Melanin is a skin pigment that protects skin by providing a physical barrier to UV and by absorbing 50%-75% of UVR. The efficacy of melanin as sunscreen was implied to be about 1.5-2.0 sun protective factors (likely as high as 4 SFP) which mean melanin absorbs 50% to 75% of UVR. Besides its protective role of melanin against the damage of UV rays, it also has antioxidant properties.

Epidemiological data strongly support the photoprotective role of melanin as there prevails an inverse relationship between skin pigmentation and the incidence of sun-induced skin cancers. Subjects with White skin are approximately 70 times more likely to develop skin cancer than subjects with Black skin.

The Harmful Role of Melanin After exposure to UVR, in vitro studies, melanin has been shown able to react with DNA and act as a photosensitizer that produces reactive oxygen species after UVA radiation that can produce single-strand DNA breaks in skin cells.

Brenner, M., & Hearing, V. J. (2008). The protective role of melanin against UV damage in human skin.Photochemistry and photobiology,84(3), 539–549. https://doi.org/10.1111/j.1751-1097.2007.00226.x

https://www.ncbi.nlm.nih.gov/pubmed/3048822/