|Year : 2021 | Volume
| Issue : 2 | Page : 95-99
The amyloid–melanin connection: a cross sectional study on primary cutaneous Macular Amyloidosis
Puneet Bhargava, Shivi Nijhawan, Heena Singdia, Rohit Garg, Neha Chepa, Deepak K Mathur
SMS Medical College and Hospital, Jaipur, India
|Date of Submission||27-May-2020|
|Date of Decision||02-Nov-2020|
|Date of Acceptance||30-Nov-2020|
|Date of Web Publication||22-Jul-2021|
Dr. Shivi Nijhawan
SMS Medical College and Hospital, 7 Dha 15, Jawahar Nagar, Jaipur, Rajasthan
Source of Support: None, Conflict of Interest: None
Context: Amyloidosis is group of rare diseases that are characterized by extracellular deposition of abnormal amyloid proteins either involving multiple organ systems (systemic amyloidosis) or restricted to a single-tissue site, such as skin (localized amyloidosis). In primary cutaneous amyloidosis, there is deposition of amyloid in apparently normal skin. The hyperpigmentation in all the lesions of primary cutaneous macular amyloidosis gives us an insight of a possibility of a connection between amyloid fibrils and melanogenesis. Aims: To compare the melanin content from the lesional skin of upper back and surrounding non-lesional skin of macular amyloidosis. Settings and Design: A hospital based, cross-sectional study conducted over a period of 6 months. Methods and Materials: Forty-two patients (30 females and 12 males) clinically and histopathologically diagnosed as macular amyloidosis were enrolled in the study. A Mexameter MX18 was used to measure the melanin index of the lesions of Macular amyloidosis over upper back and non-affected similar areas (control). Results: The melanin index of the lesional skin of female patients ranged from 552 to 823 (mean = 705.1). The melanin index of the lesional skin of male patients ranged from 621 to 792 (mean = 697.41). In the non-affected surrounding skin of females, the mean melanin index was 357.66, whereas in males, the melanin index of the surrounding normal skin was 296.75. The P value came out to be significant, that is, <0.05 in both males and females. Conclusions: There is a possible connection between amyloid fibrils and melanin synthesis. Amyloid protein in primary macular cutaneous amyloidosis may act as the precursors for melanogenesis.
Keywords: macular amyloidosis, melanin index, Mexameter
|How to cite this article:|
Bhargava P, Nijhawan S, Singdia H, Garg R, Chepa N, Mathur DK. The amyloid–melanin connection: a cross sectional study on primary cutaneous Macular Amyloidosis. Pigment Int 2021;8:95-9
|How to cite this URL:|
Bhargava P, Nijhawan S, Singdia H, Garg R, Chepa N, Mathur DK. The amyloid–melanin connection: a cross sectional study on primary cutaneous Macular Amyloidosis. Pigment Int [serial online] 2021 [cited 2021 Aug 3];8:95-9. Available from: https://www.pigmentinternational.com/text.asp?2021/8/2/95/322033
| Introduction|| |
The term “amyloid” was coined by Rudolph Virchow in 1854 to describe tissue deposits that stained like cellulose when exposed to iodine. Even though these precipitates are proteins, and not carbohydrates, the term “amyloid” is still used.
Although the amyloid proteins can be derived from a variety of different proteins, they share a common property—staining with congo red dye giving an apple-green birefringence under polarized light. Amyloid proteins differ from the physiological proteins by misfolding into aggregates with a specific beta pleated sheet configuration.
Amyloidosis is group of rare diseases that are characterized by extracellular deposition of abnormal amyloid proteins either involving multiple organ systems (systemic amyloidosis) or restricted to a single-tissue site (localized amyloidosis)., Localized or organ limited amyloidosis can be classified into cutaneous amyloidosis, endocrine, and cerebral amyloidosis.
In primary cutaneous amyloidosis (PCA), there is deposition of amyloid in apparently normal skin, without the involvement of internal organs.
PCA can be classified into three main categories: macular amyloidosis, lichen or papular amyloidosis, and nodular or tumefactive amyloidosis. Coexistence of macular and papular forms is seen in some individuals, which is termed biphasic amyloidosis.
Macular amyloidosis was first described by Palitz and Peck in 1952.
Clinically, macular amyloidosis presents as poorly delineated hyperpigmented patches of grayish-brown macules with a rippled pattern.
Secondary cutaneous amyloidosis is characterized by the presence of amyloid deposits in association with various cutaneous tumors such as basal cell carcinoma, squamous cell carcinoma, seborrheic and actinic keratoses, Bowen’s disease, porokeratosis, and skin treated with UVA radiation (320–400 nm) after the ingestion of psoralens.
The hyperpigmentation in all the lesions of PCA gives us an insight of a possibility of a connection between amyloid fibrils and melanogenesis. Our study is an attempt to find out whether melanin plays an important role in pigmentation of macular amyloidosis and to compare the melanin content or melanin indices from the lesional and surrounding nonlesional skin of macular amyloidosis.
| Subjects and methods|| |
This was a hospital based, cross-sectional study conducted over a period of 6 months from January 2019 to June 2019. Forty-two patients (30 females and 12 males) clinically diagnosed as macular amyloidosis attending the out-patient clinic of our tertiary health care institution were enrolled in the study. The cases were confirmed by skin biopsy and stained by Congo red.
The study design was approved by the Institute’s Ethics Committee and a written informed consent was obtained from patients prior to enrolment.
A Mexameter MX18 (Courage and Khazaka, Germany) was used to measure melanin content and melanin index in the lesions of macular amyloidosis over upper back and non-affected similar areas. Data were collected and fed into Excel sheets and results were obtained.
The results were summarized and presented as proportions (%). Chi-square test was used to compare abnormal findings. P value ≤ 0.05 was taken as significant. Medcalc 16.4 version software was used to analyse data presented as proportion.
Instrument and melanin index measurement
The Mexameter MX 18 is a very easy and quick tool to measure the two components, mainly responsible for the color of the skin: melanin and hemoglobin (erythema) by reflectance.
The probe of the Mexameter MX 18 emits three specific light wavelengths. A receiver measures the light reflected by the skin. As the quantity of emitted light is defined, the quantity of light absorbed by the skin can be calculated. Melanin is measured by two specific wavelengths (red: 660 nm and infrared: 880 nm) chosen to correspond to different absorption rates by the pigment.
Measurement units include arbitrary Mexameter units (0-999 for melanin and erythema).
| Results|| |
Out of the total 42 patients, 30 were females (65%) and 12 were males, thus showing female preponderance (2.5:1).
The age group of the patients varied from 18 to 55 years. All the 42 patients had lesions of macular amyloidosis on upper back. Seven patients (four females and three males) had involvement of the neck region also. Additionally, two male patients had involvement of upper limb and seven female patients that of lower limb. Melanin index was calculated from the lesions of upper back in all the patients and compared with surrounding normal skin.
The melanin index of the lesional skin of female patients ranged from 552 to 823 (mean = 705.1). The melanin index of the lesional skin of male patients ranged from 621 to 792 (mean = 697.41).
In the non-affected surrounding skin of females, the melanin index ranged from 280 to 490 (mean = 357.66), whereas in males, the melanin index of the surrounding normal skin was 296.75. The P value came out to be significant, that is, <0.05 in both males and females.
[Figure 1] and [Figure 2] compare the melanin content of the lesional and surrounding normal skin in females and males, respectively.
| Discussion|| |
PCA is characterized by deposition of amyloid in apparently normal skin, and can be classified as macular amyloidosis, lichen amyloidosis, and nodular amyloidosis. Not infrequently, features of lichen and macular amyloidosis may coexist and are termed as biphasic amyloidosis., Some unusual variants such as widespread diffuse hyperpigmentation without papules but poikilodermalike involvement, lesions following Blaschko’s line, and so forth, have also been reported.
Macular amyloidosis clinically presents as small brownish macules with a characteristic reticulated or rippled pattern, that may coalesce to form poorly circumscribed hyperpigmented lesions. The common sites of occurrence are upper back, (interscapular areas) and extremities (shins and forearms).,
Female preponderance has been consistently reported in the literature,,, as in our study, which could have a genetic basis, except for a study by Black et al. that reported more males to be affected.
Normally the multiple steps involved in amyloidogenesis is linked to many pathological conditions such as rheumatoid arthritis, systemic tuberculosis, Alzheimer, Parkinson, and Huntington disease. Nonpathological amyloid had not been detected until a study by Fowler et al. demonstrated a functional role of amyloid protein; an abundant mammalian amyloid structure that functions in melanosome biogenesis. This finding since then challenged the current view that amyloid in mammals is always pathogenic and gave an insight on the possibility of a connection between amyloid fibrils and melanogenesis.
In the above study conducted by Fowler et al., a highly enriched melanosome fraction from homogenates of bovine retinal pigment epithelium was prepared as the first step. These purified melanosomes contained Mα, a cleaved product of pmel17 fibril that showed fluorescence on using amyloid selective fluorophores thioflavin S and Congo red. This finding strongly suggested that Mα fibers in melanosomes are amyloid. A recombinant Mα amyloid (rMα) was utilized to further investigate the function of Mα amyloid fibers in melanogenesis. An in vitro assay was employed utilizing tyrosinase, 3,4-dihydroxyphenylalanine and rMα that recapitulates melanin formation within the melanosome. A time course revealed that rMα amyloid hastens the formation of insoluble melanin when added to the melanization assay, resulting in more melanin per unit time. In the same study, pmel 17 amyloid protein was compared to Aβ, synuclein amyloid fragments, and collagen, to see whether they also increase the melanogenesis process. It was found that other amyloid fragments such as Aβ and synuclein had the potential to increase melanogenesis, while collagen did not enhance the melanin formation.
The melanosome-associated structural protein Pmel17 is cleaved in normal melanosomes into two fragments, called Mα and Mβ . Maturation of eumelanosome depends on the cleavage of this fibrillar matrix protein, and it is fragment Mα that self-assembles to form the striatial fibrils within the early stage eumelanosomes. These luminal Pmel17 fibers are believed to function in polymerization of intermediates in the synthesis of melanin, [Figure 3]. We already know that cytokeratin filaments form the amyloid protein in the lesions of primary cutaneous macular amyloidosis, which has been consistently proved by immunohistocytochemistry by many researchers. We hypothesize here that this cytokeratin amyloid may act as an assembly fragment for melanin synthesis in primary cutaneous macular amyloidosis by a similar mechanism as described in an in vitro study by Fowler et al. on Pmel17, Aβ, and synuclein amyloid fragments.An ultrastructural study done by Schepis et al. on primary macular amyloidosis revealed amyloid deposits and melanosome aggregates in dermal macrophages as a consistent finding, supporting our hypothesis that the amyloid protein in primary macular cutaneous amyloidosis may act as the precursor for melanogenesis by the same mechanism described above.
It is intriguing to know that any mutation in Pmel17 and some proprotein convertase furin, leads to defect in Mα amyloid formation resulting in the loss of melanosomal membrane integrity, resulting in the formation of pores that span the membrane. This is an important pathogenic finding observed in melanoma.,
Many treatment options for PLCA have been suggested that include topical and systemic corticosteroids, phototherapy, electrodessication, dermabrasion, cryosurgery, and lasers, giving variable results.
The amyloid–melanin connection hypothesis suggests several diverse line of treatment options for pigmentation of macular amyloidosis. Use of strong antimelanotic agents such as hydroquinone, retinoids, flavonoids, azelaic acid, niacinamide, kojic acid, arbutin, mequinol, and N-acetyl-4-S-cystaminophenol should be considered as the first line of treatment.
Laser treatments targeting melanin such as Q-switched lasers and chemical peels such as mandelic acid and lactic acid can also serve as promising options.
Financial support and sponsorship
Conflicts of interest
The authors reported no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]