Exogenous ochronosis (EO) is a cutaneous disorder characterized by blue-black pigmentation resulting as a complication of long-term application of skin-lightening creams containing hydroquinone but may also occur due to topical contact with phenol or resorcinol in dark-skinned individuals. It can also occur following the use of systemic antimalarials such as quinine. EO is clinically and histologically similar to its endogenous counterpart viz., alkaptonuria, which, however, exhibits systemic effects and is an inherited disorder. Dermoscopy and in vivo skin reflectance confocal microscopy are noninvasive in vivo diagnostic tools. It is very difficult to treat EO, a cosmetically disfiguring and troubling disorder with disappointing treatment options.

Introduction

The term ochronosis is derived from the word “ochre” in Greek language, which refers to yellow discoloration.[]

Ochronosis is an uncommon disorder characterized by a clinical appearance of blue-black or gray-blue pigmentation, which reflects the histological finding of yellow-brown deposits in the dermis.[] It most commonly affects the skin and sometimes the cartilages of ears and sclera of eyes.

There are two types of ochronosis:

  • Endogenous that is, alkaptonuric ochronosis

  • Exogenous ochronosis (EO)

EO also called alkaptonuria or “black urine disease” is an inherited autosomal recessive disorder caused by a defect mapped on chromosome 4q23 that renders the enzyme homogentisate 1,2 dioxygenase inactive. This leads to the accumulation of homogentisic acid (1,2-dihydroxyphenolacetic acid, HGA) in the liver. HGA is a colorless phenolic acid that is soluble in water that accumulates in blood and is polymerized into brownish-black pigments which accumulate in connective tissues. HGA binds irreversibly to dermal fibrillar collagen which is said to be responsible for skin pigmentation, cardiopathy and/or arthropathy. It is characterized by predominant musculoskeletal manifestations. Extra-articular involvement is in the form of ocular symptoms, skin pigmentation, cardiac involvement, and genitourinary system involvement.[,,,,,] In the urine, HGA is oxidized by the oxygen in the air into benzoquinone acetate (BQA). Urine is normal in color when freshly passed, but on exposure to air BQA rapidly darkens urine to assume brownish-black color. Alkalinization of the urine increases the rate of oxidation. It reduces cupric oxide and also silver nitrate solution.[,,,,,] This forms the basis of an important bedside screening test which will differentiate alkaptonuria from EO.[]

EO is an acquired condition and is clinically and histologically similar to alkaptonuria. It has no systemic manifestations. It presents as asymptomatic bilaterally symmetrical speckled blue-black macules and several gray-brown macules, previously described as “caviar-like” bodies, typically affecting the malar areas, temples, lower cheeks, and neck. Papular and nodular lesions may also be seen. It most commonly results from the use of topical hydroquinones (usually used as bleaching creams) but has also been associated with the use of phenol, quinine injection, resorcinol, picric acid, mercury, and oral antimalarials.[,,,]

History

The term ochronosis was described by Virchow in 1866,[] referring to a brownish-yellow pigment (ochre), that was deposited in the connective tissue of various organs. EO was first described in 1906 by Pick.[] In 1912, Beddard and Plumtre,[] described the disease when a patient used phenol for the treatment of an ulcer on the leg. In 1975, Findlay and De Beer[] described EO in patients that used topical lightening agents containing hydroquinone.

Epidemiology

The global scenario

The exact incidence of EO is not known. The worldwide incidence has been assumed to be low.

There were many early reports on EO mainly from South Africa. In fact, the largest series of cases was from South Africa.[,,,,] EO was described in 28–35% of black population. It was then thought that the condition is reported exclusively among dark-skinned African individuals. However, recently published reports show that the condition is also seen in many fair-skinned individuals such as Europeans and Hispanics.[,] The condition is reported correspondingly low in the USA.[]

The exact epidemiological figures are not available except for the US, which mentions an incidence of 22 cases in more than 50 years.[]

The clinical diagnosis may be missed in early stages where it may mimic melasma. The diagnosis may not be confirmed in a number of patients due to lack of skin biopsy findings. This might have led to under-reporting of the cases of EO. Thus, the actual incidence of EO might be much higher than that reflected in the global literature.

The Asian scenario

The incidence is said to be low in Asians, but cases are increasingly being reported from India,[,,,] China,[] Thailand,[] Singapore.[,] In a recent case series from Singapore, Tan described 15 new cases in 5 year duration.[] This indicates that EO may occur across a wide spectrum of skin types, from type II or III[] to type V, and thus, is not limited to darker skin types. Recent increasing reports might be due to increased awareness of the condition.

The Indian scenario

First case of EO was reported by Zawar and Mhaskar[] from Maharashtra, India (and possibly from South-East Asia) in 2004 in a female farmer, who developed EO after unsupervised application of 4% hydroquinone-containing preparation for more than 3 months for melasma. Subsequently, few more case reports from other parts of India have emerged on PubMed described by Gandhi et al.[] and Jain et al.[] Gandhi et al. reported a case of 50-year-old women who developed EO 2–5% of hydroquinone for a prolonged duration. A similar case of EO was reported by Jain et al. in which patient developed EO on the prolonged application of triple combination de-pigmentating agents. In all these reports, unsupervised usage of skin-lightening agents was a common highlighting feature.

Etiology and Predisposing Factors

Various factors necessary for the development of EO are unprotected prolonged sun-exposure, prolonged use of skin-lightening agents mainly containing hydroquinone and, presence of a number of viable melanocytes, as suggested by Hull and Procter.[] Outdoor occupation, application of hydroquinone over a larger area or whole body and/or applying hydroquinone in large quantity may also predispose to this condition.

EO has been reported following long-term application of skin-lightening creams which contains hydroquinone, phenol or resorcinol. Of these, hydroquinone has the strongest association and was described by Findlay et al.[] in 1975. The condition is due to continual use of hydroquinone, generally, in higher concentrations more than 2%. An alcoholic solution containing hydroquinone preparations are said to more readily predispose to EO than creams.[]

Some of the recent reports mention the occurrence of EO even with as low concentrations of hydroquinone as 2%.[]

The lesions may develop gradually over 6 months to 3 years or longer.[] Two recent case reports from India mention the occurrence of EO with use of 2% hydroquinone preparations for 7–8 years.[,,] All these reports, unsupervised usage of skin-lightening agents containing hydroquinone was a common highlighting feature.

Pathogenesis

The exact pathogenesis of EO is not known. Hydroquinone interferes with skin pigmentation by inhibiting tyrosinase enzyme thereby blocking the synthesis of melanin. It also inhibits synthesis of DNA and RNA.[] Various theories put forth are speculative to explain the pathogenesis of EO. Findlay et al.[] suggested that with prolonged use, hydroquinone passes down in the papillary dermis where the drug is engulfed by the fibroblasts. This leads to attachment of phenolic degradation products and subsequent polymerization of in collagen and elastic fibers. Sun exposure and thorough inunction of the topical preparations were said to result in more advanced changes.[]

In 1983, Cullison et al.[] theorized that hydroquinone is oxidized to quinine and forms hydroxylated indoles which is similar to melanin precursors.

In 1984, Engasser[] believed that hydroquinone in higher concentrations stimulates melanocytes thereby producing more melanin.

However, the most accepted theory till date for the pathogenesis of EO was put forth by Penneys[] stating that the hyper-pigmentation is due to local competitive inhibition of the enzyme homogentisic oxidase by hydroquinone, which leads to local accumulation of homogentisic acid and its metabolic products that polymerizes to form the so-called typical ochronotic pigment in the papillary dermis [Flow diagram 1].

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Speculated pathogenesis of EO

Clinical Features

EO manifests as hyper-pigmentation in the photo-exposed regions.[] It occurs over osseous surfaces[] often affecting the zygomatic[,] regions in a symmetrical pattern. The lesions are gray-brown or blue-black macules usually with hyperchromic, pinpoint, and caviar-like papules[] [Figures [Figures113].

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Lesion on face showing brownish-black macules

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Lesion showing caviar-like papules and reticulate pigmentation

The most initial clinical classification was suggested in 1979 by Dogliotti and Leibowitz.[] They described EO in three clinical stages as follows:

Stage I – Erythema and mild hyper-pigmentation: This stage might be clinically indistinguishable from melasma [Figure 2]

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Exogenous ochronosis overlying melasma

Stage II – Progressive hyper-pigmentation pigmented colloid milium (caviar-like lesions) and scanty atrophy

Stage III – Papulonodular (sarcoid-like) lesions.

In 1986, Phillips et al.[] graded and described the condition as:

Mild – Coarsening and darkening of the skin

Moderate – Large black papules; skin in between papules is of normal pigmentation

Severe – Larger, coalescing, caviar-like papules, which are relatively dark in color.

In 1989, Hardwick et al.[] in their epidemiological study based on clinical diagnosis graded EO as:

Grade I – Faint macular sooty pigmentation

Grade II – Distinct macular stippling/small papules

Grade III – Dark deposits and papules

Grade IV – Colloid milia (1 mm and greater) [Figure 4]

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Lesion showing colloid milium

Grade V – Keloid-like nodules and cysts.

In 1991, Jordaan and Van Niekerk[] described two extremes of EO. The milder variant characterized by coarsening and darkening of skin and the severe one with caviar-like black papules and skin atrophy.

Diagnosis

Most of the diagnostic dilemma arises when EO presents in early stages in Asian and ethnic Chinese individuals where it is taken as melasma, and then treated with hydroquinone-containing products, thus leads to further aggravating of the condition. Furthermore, treatment of preexisting melasma with retinoids and/or topical steroid may also result in erythema and telangiectasias.[]

Wood's lamp examination and ultraviolet light photography are noninvasive techniques for differentiating melasma and EO but have not provided promising results as the two conditions can co-exist.[]

CharlĂ­n et al.[] and Sandra et al.[] demonstrated in dermoscopy of patients with EO, dark brown globules and globular-like structures on a diffuse brown background. In contrast, in patients with melasma a fine brown reticular pattern on a background of a faint light brown, structure-less area was noted. However, the problem is these two conditions can co-exist. Dermoscopic differential diagnosis also included nevus of ota.[]

Hence, it was not worthwhile to entirely rely on dermoscopy for the diagnosis of EO.

Gil et al.[] further suggested the superiority of reflectance confocal microscopy as an emerging noninvasive tool in the diagnosis of EO. They demonstrated the presence of hyporefractile oval-to-banana-shaped spaces in the dermis which corresponded to the banana-shaped bodies on histopathology.

Histopathology, although invasive, remains a gold standard in the diagnosis of EO, and confirms it beyond doubt. The pathognomic histopathological feature is the presence of the ochre-colored, banana-shaped fibers in the dermis. Homogenization and swelling of collagen bundles in the papillary and reticular dermis may also be seen[,] [Figures [Figures55 and and6].6]. Speckled macular lesions or early caviar-like papules are preferred lesions for a skin biopsy to yield more accuracy.

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H and E stain (×40) showing banana-shaped structure

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H and E stain showing banana-shaped structure

Treatment

EO has remained a very difficult condition to treat. Despite several modalities of treatments available, the results are often inconsistent, unpredictable and are often far from gratifying.

There are various modalities available for treatment as follows.

Nonpharmacological measures

Most important step is to stop the further use of the offending agent. Avid sun-protection is said to be a help in the prevention of further progress of the condition to some extent. Wide-brim hats, sun-goggles and appropriate sun-protective clothing are equally important.

Pharmacological treatments

Physical sunblocks and chemical sunscreens widely help in clinical improvement of the skin lesions of EO, especially when combined with the other pharmacological and procedural approaches.[,] Topical retinoid acid, glycolic acid, and a topical corticosteroid (low-potency creams) used judiciously often lead to considerable improvement in pigmentation.[] A solitary case report suggested the efficacy of tetracycline in the clearance of papular sarcoid-like ochronosis.[] Antioxidants, high doses of Vitamin E and C, may assist dilution of the pigment. Both Vitamin C and Vitamin E act as de-pigmentating agents. Both act synergistically along with antioxidants to provide photoprotection.[]

Procedural treatments

Chemical peeling with glycolic acid or tricarboxylic acid has been used for the treatment of EO shows improvement in pigmentation.[] Few patients were treated with derma-abrasion.[,] One case report mentions combination treatment of derma-abrasion and CO2 laser showing improvement.[]

In one study done, two patients with EO were treated with a Q-switched 755-nm alexandrite laser at fluence of 6–8 J/cm2 showed progressive lightening of pigmentation of the lesional skin and decreased dermal pigmentation on histological examination.[] Q-switched alexandrite laser is believed to enhance the clearance of ochronotic pigment fibers from dermis. The Q-switched ruby laser was also used in another study which showed improvement. Kramer et al.[] treated EO in a Hispanic woman with Q-switched 1064-nm neodymium-doped yttrium aluminium garnet (Nd: YAG) laser with satisfactory results. In another study, histologically proven cases of EO were treated with Q-switched Nd: YAG laser which showed satisfactory improvement in dyschromia.[]

Safety of Hydroquinone as Used in Cosmetics

Information about safety and efficacy of hydroquinone indicates that it is absorbed dermally in both aqueous and alcoholic form. Its excretion is through glucuronide or sulfate conjugates. When assessed in animals, it was found to alter immune function both in vivo and in vitro and was associated with increased incidence of renal tubular cell tumors and leukemia. Quantitatively, the use of hydroquinone in cosmetics is unlikely to cause renal tubular cell tumor. Therefore, it is safe to use hydroquinone in nail adhesives and hair dyes at a concentration of ≤1%. It should not be used in other leave-on cosmetics.[]

To summarize, EO is an underdiagnosed clinical entity, and its diagnosis is frequently missed in clinical practice. It is common in dark-skinned individuals and is increasingly being reported even in the fair-skinned individuals. Hydroquinone containing topical depigmenting agents is the leading cause of EO, especially when used for longer duration. Despite wide variety of treatment options available, treatment of EO is still unsatisfactory. The success of treatment is elusive even to the best therapeutic hands and is, therefore, remains a challenge to dermatologists. Hence, it is essential that the condition is suspected at an appropriate time, which might lead to the cessation of the progress of the condition.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

What is new?

  • Reflectance confocal microscopy as an emerging noninvasive tool in the diagnosis of EO

  • Q switch Nd Yag laser may be useful in certain patients of EO, those not responsive to medical line of therapy

  • Dermatologist's supervision during hydroquinone treatment is important to early diagnosis and prevention of EO

  • Hydroquinone content in cosmetics should be less than 1%.

Multiple Choice Questions

  1. Which of the following is synonymous with endogenous ochronosis?

    1. Alkaptonuria

    2. Black urine disease

    3. Both a and b

    4. None of the above.

  2. Most common drug implicated in causing exogenous ochronosis

    1. Hydroquinone

    2. Picric acid

    3. Antimalarials

    4. Phenol.

  3. Pathogenesis involved in exogenous ochronosis is

    1. Stimulation of melanocytes by hydroquinone

    2. Inhibition of homogentisic oxidase

    3. Oxidation of hydroquinone to products similar to melanin precursors

    4. All the above.

  4. Which of the following is necessary for development of exogenous ochronosis

    1. Sun-exposure

    2. Prolonged exposure to skin-lightening agents

    3. Viable number of melanocytes

    4. All the above.

  5. Which of the following is not the manifestation of exogenous ochronosis

    1. Hyperchromic caviar-like papules

    2. Colloid milia

    3. Macular depigmentation

    4. Keloid-like nodules and cysts.

  6. According to Dogliotti and Leibowitz clinical stages of exogenous ochronosis, stage II involves

    1. Erythema

    2. Papulonodular lesion

    3. Caviar-like lesions (pigmented colloid millium)

    4. Keloid-like nodules and cysts.

  7. Most promising noninvasive technique for diagnosis of exogenous ochronosis

    1. Reflectance confocal microscopy

    2. Dermatoscopy

    3. Wood's lamp examination

    4. Ultraviolet light photography.

  8. Pathognomic histopathologic feature of exogenous ochronosis

    1. Homogenization of collagen

    2. Banana-shaped, ochre colored fibers

    3. Increased collagen

    4. Transepidermal elimination of collagen.

  9. Agent not used in treatment of exogenous ochronosis

    1. Sunscreens

    2. Topical retinoids

    3. Glycolic acid

    4. Phenolic acid.

  10. True about hydroquinone and ochronosis is

    1. Does not occur with the use of 2% hydroquinone

    2. Develops after stopping hydroquinone

    3. Occurs due to continual use, not necessarily in higher concentration

    4. Occurs with short-term application.