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Therapeutics in Dermatology
A reference textbook in dermatology
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Ochronosis

8 October 2012, by BENMOUSLY-MLIKA R. & MOKHTAR I.

Ochronosis is the bluish black discoloration of the skin and mucosa.

Its causes may be exogenous or endogenous (alkaptonuria).

Endogenous ochronosis, also called alkaptonuria or “black urine disease” is an inherited autsomal recessive disorder caused by a defect that renders the enzyme homogentisate 1,2-dioxygenase (HGD) inactive. This leads to the accumulation of homogentisic acid (HGA) in the liver. Homogentisic acid is a colourless phenolic acid that is soluble in water that accumulates in blood and is excreted in the urine. In the urine, HGA is oxidized by the oxygen in the air into benzoquinone acetate (BQA). It is then polymerised into brownish-black pigments which accumulate in connective tissues.

A recent review of the literature showed that the incidence of endogenous ochronosis is estimated at around 5.75 cases/year with a M/F sex ratio of 1.86; its distribution is ubiquitous [1].

The disease is characterised by the presence from birth of “alkapton” HGA in the urine, causing it to become a characteristic blackish-brown colour after a few hours of contact with the oxygen in the air (first stage of the disease). Disease progression is often observed when patients are between 20 and 30 years of age and is characterised by the bluish discoloration of the ear cartilage and brownish discoloration of the ocular tissue. These alterations in skin hue are then followed by alkaptonuric arthritis, appearing between the ages of 40 and 60 and representing the third stage of this progressive disease. The arthritis mainly affects the shoulder, knee, hip joints and the spine [2]. 

The diagnosis of alkaptonuria may be confirmed by assay of HGA in the urine and/or blood.

Patients presenting with alkaptonuria can hope to have a normal life span. However, ochronotic joint, cardiovascular or renal complications may be life-threatening and affected patients should undergo monitoring of systemic parameters, especially from the age of forty [1].

The purpose of treatment is to prevent life-threatening complications.

Symptomatic treatment is often prescribed for the arthritic symptoms and valvular heart disease (antalgics, anti-inflammatories and surgery).

The results obtained with treatments referred to as aetiological, i.e. low-protein diet (1.3 g/kg/j) and ascorbic acid, have not been conclusive, but no randomised studies have been performed to confirm/contradict the findings [3]. Nitisone appears to be a treatment option given that it selectively inhibits an enzyme that catalyzes the formation of HGA [4].

Exogenous ochronosis is most frequently caused by prolonged application of hydroquinone-based topical agents. However, other substances such as phenol or quinine injections and resorcinol may also produce exogenous ochronosis. These topical agents act by inhibiting HGA oxidase. HGA accumulates in the dermis and is then polymerised to form pigment deposits.

The disorder is most often described in Black subjects because of the frequent use of hydroquinone in this population for skin lightening purposes. It is also reported in patients treated for melasma with hydroquinone for prolonged periods, especially in patients with dark skin types [5].

Clinically, exogenous ochronosis presents as grey-blue pigmented patches covering the malar (Figure 1), temple and neck areas [6].

The disease develops in three stages:

- stage I : characterised by erythema and mild hyperpigmentation;

- stage II : characterised by hyperpigmentation, colloid milium lesions and a few atrophic areas;

- stage III : characterised by papular-nodular lesions with or without inflammation [7].

Diagnosis can be confirmed by anatomopathological examination which reveals yellow-brown banana-shaped deposits in the papillary dermis that may be associated with oedema of the collagen fibres (Figure 2) and moderate histiocytic infiltration. Inflammatory sarcoidal granulomas with ochronotic particles in multinucleated giant cells have been reported [8]. The deposits are formed by accumulation of pigments around collagen or elastic fibres or in the melanocytes. The deposits become black with Fontana staining and blue with methylene blue staining.

Other non-invasive techniques may also be used for the diagnosis of ochronosis such as dermoscopy which reveals irregular brownish-grey annular and arciform structures in the ochronotic lesions. In some areas, the arciform and annular structures can be found around the follicular orifices. When confocal microscopy is used, the epidermis shows a honeycomb pattern. At the dermoepidermal junction, typical refractile basal cells may be observed corresponding to physiological hyperpigmentation of the basal layer. At the dermal level, hyporefractile oval to banana-shaped spaces that correspond to the deposits observed on histological sections may be observed next to the inferior portion of the hair follicles [9].

Treating ochronosis is not easy and treatment should mainly be preventive: it is essential to use low concentrations of hydroquinone combined with photoprotective measures and treatment should be discontinued if no improvement is observed after 6 months [10].

Use of cryotherapy and trichloracetic acid has been found ineffective. Retinoic acid has been found to improve lesions, but not consistently.

The use of mild dermocorticoids combined with photoprotective measures has been found to produce good results [6].

Other treatments such as surgical peeling, CO2 laser resurfacing, glycolic acid peeling and Q-switched laser produce inconsistent and unpredictable results [6, 7, 10, 11].

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