REVIEW ARTICLE

Exogenous Ochronosis
Prachi A Bhattar, Vijay P Zawar1, Kiran V Godse, Sharmila P Patil, Nitin J Nadkarni, Manjyot M Gautam

Abstract From the Department of

Exogenous ochronosis (EO) is a cutaneous disorder characterized by blue‑black pigmentation Dermatology,
resulting as a complication of long‑term application of skin‑lightening creams containing Dr. D. Y. Patil Hospital and
Research Institute, Nerul,
hydroquinone but may also occur due to topical contact with phenol or resorcinol in
Navi Mumbai, 1Skin Diseases
dark‑skinned individuals. It can also occur following the use of systemic antimalarials Centre, Nashik, Maharashtra, India
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 Address for correspondence:
tools. It is very difficult to treat EO, a cosmetically disfiguring and troubling disorder with Dr. Prachi A Bhattar,
Department of Dermatology,
disappointing treatment options.
Dr. D. Y. Patil Hospital and Research
Institute, Sector 5, Nerul, Navi
Key Words: Exogenous ochronosis, hydroquinone, melasma
Mumbai ‑ 400 706, Maharashtra,
India.
E‑mail: drprachibhattar@
gmail.com

What was known?

EO is an under‑diagnosed and frequently missed condition in clinical practice. A high degree of suspicion is necessary to recognize this condition.

Introduction which is said to be responsible for skin pigmentation,

The term ochronosis is derived from the word “ochre” in
Greek language, which refers to yellow discoloration.[1]
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.[2] 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
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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.[1‑6] 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.[1‑6] This forms the
basis of an important bedside screening test which will
differentiate alkaptonuria from EO.[7]
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
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How to cite this article: Bhattar PA, Zawar VP, Godse KV, Patil SP,
Nadkarni NJ, Gautam MM. Exogenous Ochronosis. Indian J Dermatol
DOI: 10.4103/0019-5154.169122 2015;60:537-43.
Received: October, 2013. Accepted: August, 2015

© 2015 Indian Journal of Dermatology | Published by Wolters Kluwer - Medknow 537

 Bhattar, et al.: Exogenous ochronosis: A review
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.[8‑11]
History
The term ochronosis was described by Virchow in 1866,[12]
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.[13] In 1912,
Beddard and Plumtre,[14] described the disease when a
patient used phenol for the treatment of an ulcer on
the leg. In 1975, Findlay and De Beer[15] 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.[16‑20] 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.[21,22]
The condition is reported correspondingly low in the
USA.[23]
The exact epidemiological figures are not available except
for the US, which mentions an incidence of 22 cases in
more than 50 years.[24]
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,[25‑28] China,[29]
Thailand,[30] Singapore.[29,31] In a recent case series
from Singapore, Tan described 15 new cases in 5 year
duration.[29] This indicates that EO may occur across a
wide spectrum of skin types, from type II or III[32] to
type V, and thus, is not limited to darker skin types.
Recent increasing reports might be due to increased
awareness of the condition.
Indian Journal of Dermatology 2015; 60(6)
The Indian scenario
First case of EO was reported by Zawar and Mhaskar[25] 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.[27] and Jain et al.[28] 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.[33] 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.[8] 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.[9]
Some of the recent reports mention the occurrence of
EO even with as low concentrations of hydroquinone as
2%.[34]
The lesions may develop gradually over 6 months to 3 years
or longer.[8] Two recent case reports from India mention the
occurrence of EO with use of 2% hydroquinone preparations
for 7–8 years.[25‑27] 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.[34] Various theories put forth are speculative
to explain the pathogenesis of EO. Findlay et al.[8]
suggested that with prolonged use, hydroquinone passes
538
 Bhattar, et al.: Exogenous ochronosis: A review
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.[8‑11]
History
The term ochronosis was described by Virchow in 1866,[12]
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.[13] In 1912,
Beddard and Plumtre,[14] described the disease when a
patient used phenol for the treatment of an ulcer on
the leg. In 1975, Findlay and De Beer[15] 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.[16‑20] 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.[21,22]
The condition is reported correspondingly low in the
USA.[23]
The exact epidemiological figures are not available except
for the US, which mentions an incidence of 22 cases in
more than 50 years.[24]
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,[25‑28] China,[29]
Thailand,[30] Singapore.[29,31] In a recent case series
from Singapore, Tan described 15 new cases in 5 year
duration.[29] This indicates that EO may occur across a
wide spectrum of skin types, from type II or III[32] to
type V, and thus, is not limited to darker skin types.
Recent increasing reports might be due to increased
awareness of the condition.
Indian Journal of Dermatology 2015; 60(6)
The Indian scenario
First case of EO was reported by Zawar and Mhaskar[25] 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.[27] and Jain et al.[28] 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.[33] 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.[8] 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.[9]
Some of the recent reports mention the occurrence of
EO even with as low concentrations of hydroquinone as
2%.[34]
The lesions may develop gradually over 6 months to 3 years
or longer.[8] Two recent case reports from India mention the
occurrence of EO with use of 2% hydroquinone preparations
for 7–8 years.[25‑27] 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.[34] Various theories put forth are speculative
to explain the pathogenesis of EO. Findlay et al.[8]
suggested that with prolonged use, hydroquinone passes
538
 Bhattar, et al.: Exogenous ochronosis: A review

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.[8]
In 1983, Cullison et al.[35] theorized that hydroquinone
is oxidized to quinine and forms hydroxylated indoles
which is similar to melanin precursors.
In 1984, Engasser[36] 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[37] stating
Figure 1: Lesion on face showing brownish-black macules
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].

Clinical Features
EO manifests as hyper‑pigmentation in the photo‑exposed
regions.[38] It occurs over osseous surfaces[39] often
affecting the zygomatic[21,40] regions in a symmetrical
pattern. The lesions are gray‑brown or blue‑black
macules usually with hyperchromic, pinpoint, and
caviar‑like papules[8] [Figures 1‑3].
The most initial clinical classification was suggested in
1979 by Dogliotti and Leibowitz.[20] They described EO in
three clinical stages as follows: Figure 2: Exogenous ochronosis overlying melasma
Stage I – 
Erythema and mild hyper‑pigmentation: This
stage might be clinically indistinguishable
from melasma [Figure 2]
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.[19] 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.[41] in their epidemiological study
based on clinical diagnosis graded EO as: Figure 3: Lesion showing caviar-like papules and reticulate pigmentation
Grade I – Faint macular sooty pigmentation
Grade II – Distinct macular stippling/small papules In 1991, Jordaan and Van Niekerk[39] described two
Grade III – Dark deposits and papules extremes of EO. The milder variant characterized by
Grade IV – Colloid milia (1 mm and greater) [Figure 4] coarsening and darkening of skin and the severe one
Grade V – Keloid‑like nodules and cysts. with caviar‑like black papules and skin atrophy.

539 Indian Journal of Dermatology 2015; 60(6)

 Bhattar, et al.: Exogenous ochronosis: A review
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.[42]
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.[42]
Charlín et al.[43] and Sandra et al.[44] 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.[44]
Hence, it was not worthwhile to entirely rely on
dermoscopy for the diagnosis of EO.
Gil et al.[22] 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[8,29] [Figures 5 and 6]. Speckled macular lesions
Figure 4: Lesion showing colloid milium
Indian Journal of Dermatology 2015; 60(6)
or early caviar‑like papules are preferred lesions for a
skin biopsy to yield more accuracy.
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.[9,45] Topical retinoid acid, glycolic
acid, and a topical corticosteroid (low‑potency creams)
used judiciously often lead to considerable improvement
in pigmentation.[9] A solitary case report suggested
the efficacy of tetracycline in the clearance of papular
sarcoid‑like ochronosis.[46] 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.[47]
Procedural treatments
Chemical peeling with glycolic acid or tricarboxylic
acid has been used for the treatment of EO shows
improvement in pigmentation.[9] Few patients were
treated with derma‑abrasion.[9,48] One case report
Figure 5: H and E stain (×40) showing banana-shaped structure
540
 Bhattar, et al.: Exogenous ochronosis: A review
Figure 6: H and E stain showing banana-shaped structure
mentions combination treatment of derma‑abrasion and
CO2 laser showing improvement.[40]
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.[49] 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.[21] 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.[50]
Safety of Hydroquinone as
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.[51]
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
Flow diagram 1: Speculated pathogenesis of EO
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?
Used in  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%.
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 Bhattar, et al.: Exogenous ochronosis: A review

Multiple Choice Questions 6. According to Dogliotti and Leibowitz clinical stages

1. 
Which of the following is synonymous with of exogenous ochronosis, stage II involves
endogenous ochronosis? a. Erythema
a. Alkaptonuria b. Papulonodular lesion
b. Black urine disease c. Caviar‑like lesions (pigmented colloid millium)
c. Both a and b d. Keloid‑like nodules and cysts.
d. None of the above. 7. Most promising noninvasive technique for diagnosis
2. Most common drug implicated in causing exogenous of exogenous ochronosis
ochronosis a. Reflectance confocal microscopy
a. Hydroquinone b. Dermatoscopy
b. Picric acid c. Wood’s lamp examination
c. Antimalarials d. Ultraviolet light photography.
d. Phenol. 8. Pathognomic histopathologic feature of exogenous
3. Pathogenesis involved in exogenous ochronosis is ochronosis
a. Stimulation of melanocytes by hydroquinone a. Homogenization of collagen
b. Inhibition of homogentisic oxidase b. Banana‑shaped, ochre colored fibers
c. Oxidation of hydroquinone to products similar to c. Increased collagen
d. Transepidermal elimination of collagen.
melanin precursors
d. All the above. 9. Agent not used in treatment of exogenous
ochronosis
4. Which of the following is necessary for development
a. Sunscreens
of exogenous ochronosis
b. Topical retinoids
a. Sun‑exposure
c. Glycolic acid
b. Prolonged exposure to skin‑lightening agents
d. Phenolic acid.
c. Viable number of melanocytes
d. All the above. 10. True about hydroquinone and ochronosis is
a. Does not occur with the use of 2% hydroquinone
5. Which of the following is not the manifestation of
b. Develops after stopping hydroquinone
exogenous ochronosis
c. Occurs due to continual use, not necessarily in
a. Hyperchromic caviar‑like papules
higher concentration
b. Colloid milia
d. Occurs with short‑term application.
c. Macular depigmentation
d. Keloid‑like nodules and cysts. Answers: 1‑c, 2‑a, 3‑d, 4‑d, 5‑c, 6‑c, 7‑a, 8‑b, 9‑d, 10‑c.

543 Indian Journal of Dermatology 2015; 60(6)