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Ochronosis | |
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Homogentisic acid | |
Specialty | Endocrinology |
Ochronosis is a syndrome caused by the accumulation of homogentisic acid in connective tissues. The condition was named after the yellowish (ocher-like) discoloration of the tissue seen on microscopic examination. Macroscopically, though, the affected tissues appear bluish-grey because of a light-scattering phenomenon known as the Tyndall effect. The condition is most often associated with alkaptonuria, but can occur from exogenous administration of phenol complexes such as hydroquinone. It was first described by Rudolf Virchow in 1865. [1]
The two types of ochronosis are endogenous and exogenous. The endogenous variety is an autosomal-recessive disease, known as alkaptonuria, that is caused by a lack of homogentisate oxidase enzyme. [2] Exogenous ochronosis is an avoidable dermatitis that can be caused by the topical application of compounds such as hydroquinone or phenols. [2] It was first seen in 1912, when a patient who used phenol on a leg ulcer was found by Beddard and Plumtre to have this condition. [3] Hydroquinone-induced exogenous ochronosis was found in 1975 by Findlay, who observed the condition in patients who used skin lightening creams containing the compound. [4]
The three clinical stages of exogenous ochronosis are: [5]
Symptoms of exogenous ochronosis include: [7]
Most of the lesions are seen on areas of the body that get the most sun. [2]
Exogenous ochronosis can be caused from long-term use of certain "skin-lightening" products, even if the hydroquinone is in amounts as small as 2%. [2] Skin-lightening products are still prevalent in many parts of the world. [8] This may be due to aesthetic or social-standing reasons, in areas where a lighter skin tone is considered to be a sign of wealth or beauty. [8] Also, skin-lightening creams containing compounds such as hydroquinone are commonly used to help with hyperpigmentation disorders such as melasma. [9]
Hydroquinone is the compound most frequently used in skin-whitening products. Due to concerns about its side effects, it was almost banned by the FDA in 2006, as medical issues of carcinogenicity and reports of disfiguring ochronosis existed. [10] In the European Union hydroquinone has been banned in cosmetic creams since 2000. [11]
Long-term use of creams containing this compound may lead to exogenous ochronotic lesions. The duration of use is directly proportional to the risk of developing the condition, with most cases occurring after years of use. [2] Around 10–15 million skin lightening products are sold annually, with Japan being the major buyer. [12]
Ochronosis occurs because of deposition of phenols (such as homogentisic acid and hydroquinone) as plaques in the matrix of cartilage. The pigments can also be incorporated into collagen and elastin fibers. In the skin, the pigment alters the structure of the fibers, causing enlargement and curling. The embedded pigments also form crosslinks with pigment depositions in adjacent fibers, stabilizing and reducing the elastic recoil of the fibers. This results in hardening of elastic structures, increasing their rigidity and brittleness. Once ruptured, the exposed pigments cause a foreign body reaction and inflammation. This pigment deposition also invokes deposition of hydroxyapatite, the mineral responsible for bone calcification, further hardening the connective tissue. The pigment can also be excreted by glandular cells in apocrine and ceruminous sweat glands, as well as breast and prostate tissue. This results in darkly pigmented sweat and breast milk. Excretion of the pigment is only found in endogenous ochronosis and should not occur from topical phenols.[ citation needed ]
The diagnosis is often made as an incidental finding intraoperatively. Cartilage exposed to the air turns dark gray or black within minutes.[ citation needed ]
Treatment is predominantly preventive. Avoidance of topical phenols and diets low in tyrosine may help.[ citation needed ] Replacement and repair of damaged tissue is also possible.
Hydroquinone-induced exogenous ochronosis is an avoidable dermatosis that is exceedingly difficult to treat. However, some studies show that treatment may be possible with a Q-switched alexandrite (755 nm) laser. [13]
Individuals with this disorder are recommended to stop using hydroquinone-containing compounds. [2] Awareness of this is important, as dermatologists may think the symptoms a patient is exhibiting are a melasma, and prescribe a hydroquinone-containing cream. [13]
Alkaptonuria is a rare inherited genetic disease which is caused by a mutation in the HGD gene for the enzyme homogentisate 1,2-dioxygenase ; if a person inherits an abnormal copy from both parents, the body accumulates an intermediate substance called homogentisic acid in the blood and tissues. Homogentisic acid and its oxidized form alkapton are excreted in the urine, giving it an unusually dark color. The accumulating homogentisic acid causes damage to cartilage and heart valves, as well as precipitating as kidney stones and stones in other organs. Symptoms usually develop in people over 30 years old, although the dark discoloration of the urine is present from birth.
Nevus is a nonspecific medical term for a visible, circumscribed, chronic lesion of the skin or mucosa. The term originates from nævus, which is Latin for "birthmark"; however, a nevus can be either congenital or acquired. Common terms, including mole, birthmark, and beauty mark, are used to describe nevi, but these terms do not distinguish specific types of nevi from one another.
Hyperpigmentation is the darkening of an area of skin or nails caused by increased melanin.
Periorbital dark circles are dark blemishes around the eyes. There are many causes of this symptom, including heredity and bruising.
Actinic keratosis (AK), sometimes called solar keratosis or senile keratosis, is a pre-cancerous area of thick, scaly, or crusty skin. Actinic keratosis is a disorder of epidermal keratinocytes that is induced by ultraviolet (UV) light exposure. These growths are more common in fair-skinned people and those who are frequently in the sun. They are believed to form when skin gets damaged by UV radiation from the sun or indoor tanning beds, usually over the course of decades. Given their pre-cancerous nature, if left untreated, they may turn into a type of skin cancer called squamous cell carcinoma. Untreated lesions have up to a 20% risk of progression to squamous cell carcinoma, so treatment by a dermatologist is recommended.
Melasma is a tan or dark skin discoloration. Melasma is thought to be caused by sun exposure, genetic predisposition, hormone changes, and skin irritation. Although it can affect anyone, it is particularly common in women, especially pregnant women and those who are taking oral or patch contraceptives or hormone replacement therapy medications.
Hydroquinone, also known as benzene-1,4-diol or quinol, is an aromatic organic compound that is a type of phenol, a derivative of benzene, having the chemical formula C6H4(OH)2. It has two hydroxyl groups bonded to a benzene ring in a para position. It is a white granular solid. Substituted derivatives of this parent compound are also referred to as hydroquinones. The name "hydroquinone" was coined by Friedrich Wöhler in 1843.
Tyrosinase is an oxidase that is the rate-limiting enzyme for controlling the production of melanin. The enzyme is mainly involved in two distinct reactions of melanin synthesis otherwise known as the Raper Mason pathway. Firstly, the hydroxylation of a monophenol and secondly, the conversion of an o-diphenol to the corresponding o-quinone. o-Quinone undergoes several reactions to eventually form melanin. Tyrosinase is a copper-containing enzyme present in plant and animal tissues that catalyzes the production of melanin and other pigments from tyrosine by oxidation. It is found inside melanosomes which are synthesized in the skin melanocytes. In humans, the tyrosinase enzyme is encoded by the TYR gene.
Anal bleaching is the process of lightening the color of the skin around the anus. It is done for cosmetic purposes, to make the color of the anus more uniform with the surrounding area. Some treatments are applied in an office or salon by a cosmetic technician and others are sold as cream that can be applied at home.
Azelaic acid (AzA) is an organic compound with the formula HOOC(CH2)7COOH. This saturated dicarboxylic acid exists as a white powder. It is found in wheat, rye, and barley. It is a precursor to diverse industrial products including polymers and plasticizers, as well as being a component of a number of hair and skin conditioners. AzA inhibits tyrosinase.
Erythema ab igneEAI, also known as hot water bottle rash, is a skin condition caused by long-term exposure to heat. Prolonged thermal radiation exposure to the skin can lead to the development of reticulated erythema, hyperpigmentation, scaling, and telangiectasias in the affected area. Some people may complain of mild itchiness and a burning sensation, but often, unless a change in pigmentation is seen, it can go unnoticed.
A lentigo is a small pigmented spot on the skin with a clearly defined edge, surrounded by normal-appearing skin. It is a harmless (benign) hyperplasia of melanocytes which is linear in its spread. This means the hyperplasia of melanocytes is restricted to the cell layer directly above the basement membrane of the epidermis where melanocytes normally reside. This is in contrast to the "nests" of multi-layer melanocytes found in moles. Because of this characteristic feature, the adjective "lentiginous" is used to describe other skin lesions that similarly proliferate linearly within the basal cell layer.
Cysteamine is a chemical compound that can be biosynthesized in mammals, including humans, by the degradation of coenzyme A. The intermediate pantetheine is broken down into cysteamine and pantothenic acid. It is the biosynthetic precursor to the neurotransmitter hypotaurine.
Skin whitening, also known as skin lightening and skin bleaching, is the practice of using chemical substances in an attempt to lighten the skin or provide an even skin color by reducing the melanin concentration in the skin. Several chemicals have been shown to be effective in skin whitening, while some have proven to be toxic or have questionable safety profiles. This includes mercury compounds which may cause neurological problems and kidney problems.
Arbutin is a glycoside; a glycosylated hydroquinone extracted from the bearberry plant in the genus Arctostaphylos among many other medicinal plants, primarily in the family Ericaceae. Applied topically, it inhibits tyrosinase and thus prevents the formation of melanin. Arbutin is therefore used as a skin-lightening agent. Very tiny amounts of arbutin are found in wheat, pear skins, and some other foods. It is also found in Viburnum opulus and Bergenia crassifolia. Arbutin was also produced by an in vitro culture of Schisandra chinensis.
Depigmentation is the lightening of the skin or loss of pigment. Depigmentation of the skin can be caused by a number of local and systemic conditions. The pigment loss can be partial or complete. It can be temporary or permanent.
Esoterica is an over-the-counter topical ointment applied to the skin for the purpose of lightening freckles, age spots, chloasma, melasma, and other skin discolorations due to a benign localized increase in the production of melanin. Esoterica may have other appropriate medical uses as determined by a physician.
Photorejuvenation is a skin treatment that uses lasers, intense pulsed light, or photodynamic therapy to treat skin conditions and remove effects of photoaging such as wrinkles, spots, and textures. The process induces controlled wounds to the skin. This prompts the skin to heal itself, by creating new cells. This process—to a certain extent—removes the signs of photoaging. The technique was invented by Thomas L Roberts, III using CO2 lasers in the 1990s. Observed complications have included scarring, hyperpigmentation, acne, and herpes.
Kyrle disease is identified as a form of an acquired perforating disease. Other major perforating diseases are elastosis perforans serpiginosa and reactive perforating collagenosis. Recently, however, there is a controversy on categorizing Kyrle disease with perforating dermatosis or a subtype of acquired perforating collagenosis.
Oral pigmentation is asymptomatic and does not usually cause any alteration to the texture or thickness of the affected area. The colour can be uniform or speckled and can appear solitary or as multiple lesions. Depending on the site, depth, and quantity of pigment, the appearance can vary considerably.