Review

Exogenous ochronosis associated with hydroquinone:

a systematic review
Stephanie Ishack1, PhD and Shari R. Lipner2, MD, PhD

1
New York University School of Medicine, Abstract
New York, NY, USA, and 2Department of Exogenous ochronosis is a potential side effect associated with hydroquinone, and treatment
Dermatology, Weill Cornell Medicine, New
is often unsatisfactory. Our study objectives were to review data on hydroquinone-associated
York, NY, USA
ochronosis to determine risk factors for patients experiencing this adverse event. On
Correspondence September 27, 2020 (MEDLINE/PubMed), and October 30, 2020 (Scopus and Web of
Shari R. Lipner, MD, PHD Science), databases were searched for “ochronosis + hydroquinone” by both authors to
1305 York Avenue reduce risk basis. PRISMA reporting guidelines were used to select 56 articles with a total of
New York,
126 patients with hydroquinone-associated ochronosis. Included articles described
NY 10021
USA
hydroquinone-associated ochronosis. Articles were excluded if they had irrelevant content,
E-mail: shl9032@med.cornell.edu were non-English language text, and were non-case studies. Full text articles were assessed
and recorded. Cross-tabulation analysis was performed on categorical data, and Fisher exact
Conflict of interest: None. test was performed. Ochronosis was most often reported in middle-aged women (53.2%), of
African descent (45.2%), Black races (55.5%), and Fitzpatrick skin types V–VI (52.4%). It was
Funding source: None. most frequently reported with unknown and hydroquinone concentrations greater than 4%
(32.5 and 35.7% cases, respectively). Median duration of use was 5 years, with only four
cases reported with courses 3 months or shorter and eight cases reported with use 1 year or
doi: 10.1111/ijd.15878
less. All patients presented with facial blue-black or gray-blue macules in a reticulate, lace-
like fashion. Histopathology consistently showed solar elastosis and brownish-yellow,
‘banana-shaped’ fibers between degenerated collagen fibers of the papillary dermis. Based
on these findings, we conclude that hydroquinone in concentrations above 4% and in
treatment courses longer than 3 months may be associated with new-onset ochronosis.

the hydroquinone 4% cream package insert, include allergic

Introduction
Hydroquinone 4% cream is approved by the United States
(U.S.) Food and Drug Administration (FDA) for treatment of
melasma, chloasma, freckles, senile lentigines, and hyperpig-
1
mentation. Hydroquinone’s mechanism of action involves: (i)
modification of melanosome formation and melanization, (ii)
copper interaction at the active site of tyrosinase, and (iii) inhibi-
tion of DNA and RNA synthesis.2 In the U.S. and Canada,
hydroquinone 4% cream is available by prescription only.1,2
Hydroquinone medications with concentrations less than 4%
were previously available over-the-counter (OTC) in the U.S.
On September 25, 2020, the FDA enforced the 2020 CARES
Act and Over-the-Counter Drug Monograph Reform, stating that
hydroquinone is not classified as Category II/not generally rec-
ognized as safe and effective (GRASE) and prohibiting the dis-
tribution of OTC hydroquinone products.3,4 Hydroquinone is not
legally available by prescription or OTC in the European Union
2
(EU), Australia, or Japan. However, a United Kingdom (UK)
news source reported that hydroquinone products were moder-
ately easy to procure.5 Potential adverse events, described in
contact dermatitis, dryness and fissuring of paranasal and
infraorbital areas, erythema, stinging, and epidermal atrophy;
ochronosis is not described.1 Hydroquinone-induced exogenous
ochronosis was first described by Findlay in 1975.6 It is charac-
terized by blue-black or gray-blue skin hyperpigmentation clini-
cally, with ochre pigmented ‘banana-shaped’ fibers on
histopathology.6-8 Since treatment of ochronosis is challenging
and unsuccessful in many cases, it is important to prevent this
adverse event. Patient demographics, concentrations, and med-
ication courses associated with hydroquinone-induced ochrono-
sis are not well-characterized. Our study objectives were to
review case studies of exogenous ochronosis associated with
hydroquinone to determine risk factors for patients experiencing
this adverse event.
Methods
Three databases were searched by two investigators for the
terms “ochronosis + hydroquinone” on September 27, 2020
(MEDLINE/PubMed), and October 30, 2020 (Scopus and Web 1

ª 2021 the International Society of Dermatology International Journal of Dermatology 2021

2 Review Ochronosis hydroquinone systematic review
of Science), yielding a total of 433 articles (Fig. 1). The
Preferred Reporting Items for Systematic Reviews and Meta-
analyses (PRISMA) reporting guidelines were used to finalize a
list of relevant articles to be included in the systematic review
with both authors performing the analysis. Included articles
described hydroquinone-associated ochronosis. Of the 433
articles, duplicate articles were removed (n = 132). Abstracts
(n = 301) were screened, and those with irrelevant content,
non-English language text, and non-case studies were excluded
(n = 199). Full text articles (n = 102) were assessed, and those
without confirmatory histopathology were excluded (n = 46).
Reference lists were reviewed from the remaining 56 articles,
and an additional article was added for analysis for a total of
57. Disagreements about included/excluded articles were
resolved by discussion or senior author decision, and the
International Journal of Dermatology 2021
Ishack and Lipner
Figure 1 PRISMA flow diagram showing
article selection process
reasons for exclusion were noted. Patient demographics,
including age, gender, race, ethnicity, skin phototype, as well as
medications/products used, duration of use, clinical indication,
clinical presentation, comorbidities, and histopathology were
tabulated. Cross-tabulation analysis was performed on
categorical data using sorting tools within Excel to identify
associations between risk of ochronosis, hydroquinone
concentrations percentages, and duration of use. Fisher’s exact
test was performed to analyze for an association between the
two categorical variables (duration used and percentage used).
Percentages were calculated for gender, race, ethnicity,
Fitzpatrick skin phototypes, and clinical indications. When a
range of hydroquinone concentrations was used, the highest
concentration was used for categorization into three groups
(less than 4%, 4%, greater than 4%). Fitzpatrick skin types
ª 2021 the International Society of Dermatology
Ishack and Lipner
were assigned by examining photographs and using a standard
classification scale.9 Images that were indeterminate because
of poor quality, lighting, or black and white photographs were
excluded. The study designs were comparable because all
evaluations were done on case studies involving qualitative
analysis methods.
Results
A total of 126 patients with hydroquinone-induced ochronosis
were included in the final analysis. Table 1 summarizes data from
case reports and case series. The average patient age was
51.5 years (range 30–75). Most patients were female (53.2%),
with 7.1% male and 40.0% unknown gender. The most frequently
represented races were Black (55.5%), Asian (27.0%) and White
(5.6%) (Fig. 2). The most common reported ethnicities were Afri-
can (45.2%), Chinese (15.1%), Brazilian (11.1%), and Indian
(8.7%) (Fig. 2). Fitzpatrick skin phototypes most commonly rep-
resented were V–VI (52.4%) and III–IV (40.0%). There were no
patients with phototypes I–II, and 7.5% were indeterminate.
Hyperpigmentation was the most common clinical indication for
hydroquinone treatment (63.4% of patients), followed by mel-
asma (24.8%) and solar lentigo (5.6%).
For many of the ochronosis cases, the hydroquinone concen-
tration was unknown (32.5%) or greater than 4% (35.7%).
Ochronosis associated with hydroquinone concentrations 4% or
less than 4% was experienced by 16.7 and 15.1% of patients,
respectively (Table 2). Median duration of usage was 5 years
(range: 2 months to 30 years). The vast majority (104/126;
82.5%) of ochronosis cases occurred in patients who applied
hydroquinone for more than 1 year, with many cases greater
than 4 years (90/126; 71.4%). There were only four cases
(3.2%) reported in patients applying hydroquinone for 3 months
or less (Table 2). A higher percentage of patients using concen-
trations greater than 4% used the medication for greater than
4 years compared to patients using <4% or 4% (100% vs. 58%
vs. 57%, respectively). The P-value from our analysis is
P < 0.0001, which is highly statistically significant. This is
mainly driven by the >4% medication group having more people
with >4 years of use compared to the other two medication cat-
egories. While several patients had comorbidities, there were
no associations between having another medical problem and
development of ochronosis; these results were confirmed by
cross-tabulating patterns and trends.
Clinical examination findings were described for all patients.
Typically, patients presented with gray-black/brown or blue-
black/brown macules involving the cheeks, nose, forehead,
chin, and eyebrows (Fig. 3). Locations including the neck, arms,
back, fingers, and toes were not commonly described in the
observed studies. Wood’s lamp examination was used in one
patient to delineate the location of pigment (epidermal, dermal
or mixed).57 Wood’s light showed partial enhancement of pig-
ment, which was confirmed by histopathology to be localized to
ª 2021 the International Society of Dermatology
Ochronosis hydroquinone systematic review Review 3
the papillary dermis. Dermoscopic findings were described for
29 patients, demonstrating irregular brown-gray amorphous
structures with fine telangiectasias. There were caviar-like
papules which were distinctive blue-grey dots and globules oblit-
erating the follicular openings.
Skin biopsies of hydroquinone associated ochronosis were
performed for all patients. Histopathology consistently showed
solar elastosis and brownish-yellow (ochre) ‘banana-shaped’
fibers between the degenerated collagen fibers of the papillary
dermis (Fig. 4). In one patient, confocal microscopy was used
to confirm that multiple banana-shaped structures corresponded
with the areas of ochronosis.37
Discussion
Our study demonstrated that exogenous ochronosis secondary
to hydroquinone is most commonly reported with unknown or
high concentrations and long treatment courses (greater than
1 year). Of note, only 15.1% of cases occurred at concentra-
tions less than 4% (two cases at 3 months or less; one case at
>3–6 months; three cases at >1–2 years; two cases at >2–
3 years, and 11 cases at >4 years), and there were only four
(3.2%) cases reported with treatment courses 3 months or less.
Our findings of hydroquinone-associated ochronosis with short
treatment courses are consistent with results from a previous
study.12 In a clinical trial evaluating treatment of 120 patients
with melasma and hyperpigmentation randomized to treatments
with hydroquinone 4% or triple combination (TC) creams (hydro-
quinone 4%, retinoic acid 0.05%, and fluocinolone acetonide
0.01%) for 8 weeks, there were no reports of ochronosis.12
Our data showing that high and unknown hydroquinone con-
centrations and longer treatment courses are possibly associ-
ated with ochronosis are consistent with results from previous
studies. Findlay et al. reported on 35 South African patients with
exogenous ochronosis who applied 6–8% hydroquinone creams
continuously for up to 8 years.6 Petit et al. reported on 5/46
patients (11%) with exogenous ochronosis who used hydro-
quinone concentrations greater than 4% for a mean duration of
12 years.13 In a study of 5,128 South African patients who used
unregulated hydroquinone agents for one year, 395 (7.7%) pre-
sented with exogenous ochronosis.14
We also found that hydroquinone-associated ochronosis was
most often reported in middle-aged women of African descent,
Black races, and Fitzpatrick skin types III–VI. The reasons for
these findings are not entirely clear. The higher frequency in
women versus men may be because of a higher prevalence of
melasma/hyperpigmentation in women or that women seek
treatment for these conditions more often than men.14-18 Since
prescribing data are unavailable, it is unknown whether there is
a physiological predilection for ochronosis in darker skin photo-
types or, alternatively, if there is more frequent hydroquinone
use or higher concentrations utilized in these populations. This
topic merits further study.
International Journal of Dermatology 2021
4 Review Ochronosis hydroquinone systematic review Ishack and Lipner

Table 1 Case reports and case series of hydroquinone-associated exogenous ochronosis

Age Skin Medications/products and percentages Duration

Reference (years)/gender phototype used (months/years) Clinical indication

ndez Baca et al.40

Me 55/female IV Undisclosed hydroquinone % 5 years Hyperpigmentation
Nagler et al.41 53/female IV Undisclosed hydroquinone % Several years Hyperpigmentation
Tan et al.42 54/female III 4% hydroquinone, tretinoin, & fluocinolone 6 years Melasma
acetonide
Tan et al.42 58/female III 4% hydroquinone 5 years Melasma
Bongiorno et al.38 35/female VI Undisclosed hydroquinone % 10 years Vitiligo
Bongiorno et al.38 45/female VI 2% hydroquinone >4 years Hyperpigmentation
Martins et al.42 64/female IV 4% hydroquinone 3 years Hyperpigmentation
Merola et al.43 55/female Unspecified Undisclosed hydroquinone % 9 months Melasma
Charlın et al.33 56/female IV Concentrations varying 2–4% hydroquinone 20 years Melasma, solar lentigo
Charlın et al.33 44/female IV Concentrations varying 2–5% hydroquinone 10 years Melasma, solar lentigo
Charlın et al.33 56/female V 6% hydroquinone 25 years Melasma, solar lentigo
Charlın et al.33 51/female V 5% hydroquinone 10 years Melasma, solar
elastosis
Ribas et al.46 36/female III 2% hydroquinone 5 years Melasma
Ribas et al.46 56/female IV Concentrations varying 2–6% hydroquinone 8 years Hyperpigmentation
Ribas et al.46 58/female IV Concentrations varying 2–5% hydroquinone 10 years Melasma
Ribas et al.46 38/female III Concentrations varying 2–4% hydroquinone 3 years Melasma
Snider et al.47 59/female IV Concentrations varying 2–3% hydroquinone Several years Hyperpigmentation
Mishra et al.9 30/male IV 4% hydroquinone TC 7 years Melasma
Mishra et al.9 30/male IV 2% hydroquinone with tretinoin and 8 years Melasma
corticosteroid
Mishra et al.9 42/male IV 4% hydroquinone 2 years Melasma
Sindhu et al.11 65/male Unspecified 3% hydroquinone 10 years Hyperpigmentation
Tan et al.54 50/unspecified III Undisclosed hydroquinone % Unspecified Hyperpigmentation
Tan et al.54 54/unspecified III 4% hydroquinone with tretinoin (Tri-Luma) 7 years Hyperpigmentation
Tan et al.54 60/unspecified IV 4% hydroquinone >20 years Hyperpigmentation
Tan et al.54 46/unspecified III Undisclosed hydroquinone % >5 years Melasma
Tan et al.54 68/unspecified IV Undisclosed hydroquinone % >5 years Hyperpigmentation
Tan et al.54 54/unspecified III 4% hydroquinone >5 years Hyperpigmentation
Tan et al.54 48/unspecified III 4% hydroquinone 2 years Hyperpigmentation
Tan et al.54 57/unspecified IV 4% hydroquinone 8 years Hyperpigmentation
Tan et al.54 38/unspecified III Undisclosed hydroquinone % 3 years Melasma
Tan et al.54 55/unspecified IV Undisclosed hydroquinone % 2 years Hyperpigmentation
Tan et al.54 44/unspecified III 4% hydroquinone 1 year Hyperpigmentation
Tan et al.54 48/unspecified III Undisclosed hydroquinone % 2 years Hyperpigmentation
Tan et al.54 53/unspecified III 4% hydroquinone with tretinoin (Tri-Luma) 5 years Hyperpigmentation
Tan et al.55 57/female IV Undisclosed hydroquinone % 5 years Hyperpigmentation
Tan et al.55 Unspecified/ III Undisclosed hydroquinone % 10 years Hyperpigmentation
unspecified
Tan et al.55 47/female III Undisclosed hydroquinone % 3 years Hyperpigmentation
Tidman et al.56 45/female VI 2% hydroquinone 10 years Hyperpigmentation,
solar lentigo
Zawar et al.57 30/female IV 4% hydroquinone >3 months Melasma
Howard et al.58 36/female IV 2% hydroquinone 4–6 months Solar lentigo
Hull et al.59 60/female VI 2% hydroquinone 2 years Vitiligo
Cullison et al.60 58/female VI 2% hydroquinone 2.5 years Hyperpigmentation
Lawrence et al.61 46/female IV 1% hydroquinone 2–3 months Hyperpigmentation
Lawrence et al.61 62/female IV 1% hydroquinone 2–3 years Solar lentigo
Pirrone et al.48 51/female V Undisclosed hydroquinone % Unspecified Hyperpigmentation
Gandhi et al.39 50/female Unspecified Concentrations varying 2–5% hydroquinone 7–8 years Hyperpigmentation
Gil et al.37 63/female V Concentrations varying 2–3% hydroquinone Several years Hyperpigmentation
Jordaan et al.62 56/male V Concentrations varying 6.5–7.5% Several years Hyperpigmentation
hydroquinone
Jordaan et al.62 39/female V Undisclosed hydroquinone 5 years Hyperpigmentation
Hoshaw et al.32 75/female VI 2% hydroquinone 2 years Hyperpigmentation

International Journal of Dermatology 2021 ª 2021 the International Society of Dermatology

Ishack and Lipner Ochronosis hydroquinone systematic review Review 5

Table 1 Continued

Age Skin Medications/products and percentages Duration

Reference (years)/gender phototype used (months/years) Clinical indication

Hoshaw et al.32 49/female VI Undisclosed hydroquinone % 3 months Hyperpigmentation

Lang et al.63 74/female IV Undisclosed hydroquinone % Several year Hyperpigmentation
Bowman et al.64 75/female VI Undisclosed hydroquinone % Unspecified Unspecified
Moche et al.65 58/female VI Undisclosed hydroquinone % Unspecified Hyperpigmentation
Moche et al.65 48/female VI Undisclosed hydroquinone % Unspecified Unspecified
Jordaan et al.66 39/female VI Undisclosed hydroquinone % Several years Hyperpigmentation
Khunger et al.10 48/female IV 2% hydroquinone 8 years Melasma
Khunger et al.10 42/female IV 2% hydroquinone, 0.025% tretinoin, 1% 13 years Melasma
hydrocortisone
Jain et al.67 45/male IV Triple cream undisclosed hydroquinone % 7 years Melasma
Liu et al.31 50/male IV Undisclosed hydroquinone % Unspecified Hyperpigmentation
Connor et al.68 72/female VI Undisclosed hydroquinone % Several decades Hyperpigmentation
Sanchez-Martınez 48/female VI 4% hydroquinone >2 years Hyperpigmentation
et al.69
Kindem et al.70 62/female V Undisclosed hydroquinone % 20 years Hyperpigmentation
Martın et al.71 44/female Unspecified Undisclosed hydroquinone % 3–4 years Unspecified
Martın et al.71 56/female Unspecified Undisclosed hydroquinone % 30 years Unspecified
Davis et al.72 40/male VI Undisclosed hydroquinone % 9 months Unspecified
Kramer et al.73 50/female VI Concentrations varying 2–4% hydroquinone 30 years Melasma
Huerta et al.74 70/female Unspecified 2% hydroquinone 6 years Melasma
Cordova et al.75 49/female Unspecified Undisclosed hydroquinone % 15 years Melasma
Diven et al.76 53/female VI 2% hydroquinone 3 months Hyperpigmentation
Romero et al.34 38/female V 4% hydroquinone 4%, tretinoin 0.05% and 5 years Melasma
dexamethasone 0.05%
Romero et al.34 57/female IV 2% hydroquinone >4 years Melasma
Romero et al.34 45/female III 4–6% hydroquinone Unspecified Hyperpigmentation
Singh et al.77 44/female IV Unspecified hydroquinone 1 year Melasma
Lee et al.78 48/female VI Undisclosed hydroquinone % Several years Melasma
Kanechorn-Na- 67/female V Undisclosed hydroquinone % Several years Melasma
Ayuthaya et al.79
Kanechorn-Na- 58/female III Undisclosed hydroquinone % Unspecified Melasma
Ayuthaya et al.79
Kanechorn-Na- 66/female IV Undisclosed hydroquinone % Unspecified Melasma
Ayuthaya et al.79
Hermawan et al.36 51/female IV Undisclosed hydroquinone % Several years Hyperpigmentation
Rodrigues et al.80 40/female III Undisclosed hydroquinone % 8 years Hyperpigmentation
Qorbani et al.81 68/female V 4% hydroquinone Several years Melasma
Qorbani et al.81 58/female IV Tretinoin 0.05% cream and 4% hydroquinone 1 year Melasma
Bellew et al.82 47/female Unspecified Undisclosed hydroquinone % Several months Unspecified
Bellew et al.82 46/male Unspecified Undisclosed hydroquinone % 1 year Unspecified
Petit et al.13 Unspecified/ V–VI Concentrations varying 4.5–16.7% 12–14 years Hyperpigmentation
unspecified hydroquinone
Maxfield et al.83 53/female III 3% hydroquinone 18 months Hyperpigmentation
Saini et al.84 29/female V 4% hydroquinone 2 years Hyperpigmentation
Le Borgne et al.85 47/female V Undisclosed hydroquinone % 2 months Hyperpigmentation
Chang et al.86 50/female V 6% hydroquinone Several years Hyperpigmentation
Tomasini et al.87 42/female IV Unspecified hydroquinone 5 years Hyperpigmentation
Desai et al.88 22/female Unspecified Unspecified hydroquinone 10 years Hyperpigmentation
Findlay et al.6 30–39 range/ VI (100%) 8% hydroquinone 8 years Hyperpigmentation
unspecified

Hydroquinone-containing beauty products are associated with
ochronosis as well as skin darkening and coarsening, black,
caviar-like papules.6,14,19,20,21,22 There were an estimated
25.0% of women in Bamako, Mali (1994), 52.7% in Dakar,
Senegal (2003), and 77.0% in Lagos (2002), Nigeria, who used
skin lighteners.21,23,24,25 Hydroquinone-induced exogenous
ochronosis has been reported commonly in South African
blacks, where its prevalence is estimated at 28–35% of the pop-
ulation.23 In South Africa, exogenous ochronosis was still
reported with high frequency even after restrictions were

ª 2021 the International Society of Dermatology International Journal of Dermatology 2021

6 Review Ochronosis hydroquinone systematic review Ishack and Lipner

Race
60.0% 55.5%

50.0%

40.0%
Percentages

30.0% 27.0%

20.0%
10.3%
10.0% 5.6%
0.8% 0.8%
0.0%
Black Asian Unspecified White Pacific Islander Nave American
Race

Ethnicity
50.0%
45.2%
45.0%

40.0%

35.0%
Percentages

30.0%

25.0%

20.0%
15.1%
15.0% 13.0%
11.1%
10.0% 8.7%

4.0%
5.0% 1.6% 0.8% 0.8%
0.0%
African Chinese Unspecified Brazilian Indian Hispanic Thai Filipino Indonesian Figure 2 Bar graphs depicting distribution
Ethnicity of ethnic and racial groups with
hydroquinone associated ochronosis

implemented in 1983 to limit availability of OTC hydroquinone
products, suggesting that hydroquinone products were obtained
from the illicit sources.24,25 When Mahe et al. surveyed 368
women following the South African hydroquinone restrictions,
194 (52.7%) reported using bleaching products, and there were
14 cases of exogenous ochronosis.20 The active compounds in
these bleaching agents included concentrations of 4–8.7%
hydroquinone (used by 89% of users), glucocorticoids (70%),
mercury iodide (10%), and caustic agents (17%); 13% used
products of unknown composition. The Black population has
been impacted greatly by the social and cultural trends empha-
sizing skin lightening24-29; both sociological and psychological
factors may be responsible for these trends.25,26 Black commu-
nities have been disproportionately affected by ochronosis,
likely because of frequent use in this population.26 Therefore,
there is a need to provide adequate information on sun protec-
tion and the potential effects of long-term use of hydroquinone
targeting this subset of patients.
As of September 25, 2020, sales of OTC hydroquinone were
5
prohibited in the U.S. because of drug reforms. Therefore, we
have serious concerns about access to safe hydroquinone prod-
ucts (4% or less), both for uninsured patients without access to
board-certified dermatologists and those who cannot afford pre-
scription strength hydroquinone. We fear that inaccessibility of
lower concentration OTC hydroquinone medications will result in
patients purchasing hydroquinone products of unknown concen-
trations, which may be more likely to cause ochronosis. In addition,
patients may seek alternative skin lightening products containing
mercury and steroids that are readily available online with more
worrisome potential adverse effects.30 On the other hand, stricter
control and policy development in banning OTC hydroquinone
products may prevent long-term misuse in Black communities.
All patients exhibiting ochronosis had consistent
histopathological morphology: yellow-brown (ochre), ‘banana-
shaped’ fibers in the dermis with background solar elasto-
sis.6,7,8,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52 Liu
et al. highlighted the importance of dermoscopy for the early
recognition of ochronosis to aid in appropriate selection of
skin biopsy sites.31 Charlin et al. observed that the ochrono-
tic pigment observed clinically and dermoscopically was blue-

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Ishack and Lipner Ochronosis hydroquinone systematic review Review 7

Table 2 Hydroquinone concentrations and duration of use with reports of ochronosis

Less than 4% 4% Greater than 4%

Duration hydroquinone hydroquinone hydroquinone Unspecified

3 months or less 2 (2/19) 0 0 2 (2/41)

>3–6 months 1 (1/19) 1 (1/21) 0 0
>6 months to 1 year 0 2 (2/21) 0 4 (4/41)
>1–2 years 3 (3/19) 4 (4/21) 0 2 (2/41)
>2–3 years 2 (2/19) 2 (2/21) 0 1 (1/41)
>4 years 11 (11/19) 12 (12/21) 44 (44/45) 23 (23/41)
Unspecified 0 0 1 9
Total (n) patients 19/126 patients 21/126 patients 45/126 patients 41/126 patients
Total % of patients 15.1% of patients 16.7% of 35.7% of patients 32.5% of
patients patients
Total % of patients who used hydroquinone for 57.9% of patients 57.14% of 97.8% of patients 56.1% of
>4 years patients patients

Figure 4 Histopathology of ochronosis in a 64-year-old woman who

Figure 3 Clinical presentation of biopsy proven ochronosis in a
black woman with Fitzpatrick type VI skin. There are gray-brown
macules of the malar cheeks. The patient used various
concentrations of hydroquinone for years. Permission to use this
clinical image was granted by Andrew F. Alexis, MD, MPH, Mount
Sinai West and Mount Sinai Morningside
gray, not ochre as in the histopathology, and that dermo-
scopic findings differed between healthy skin, melasma, and
ochronotic areas. 33
Dermoscopy is a valuable complementary
tool to clinical examination for diagnosing exogenous
ochronosis thereby reducing unnecessary skin biopsies.33-37
Exogenous ochronosis consists of three clinical stages, as
described by Dogliotti and Leibowitz: (i) initial erythema and
mild pigmentation change; (ii) followed by hyperpigmentation,
black colloid milia, and atrophy; and (iii) lastly papulonodules.52
used hydroquinone for many years. The collagen bundles have a
swollen ochre-like appearance and focally are associated with
foreign body reaction. The pigment alteration is largely confined to
the superficial dermis (Hematoxylin-eosin stain 9 40). Permission to
use this clinical image was granted by Cynthia Magro, MD, Weill
Cornell Medicine
Several theories have been proposed to explain the mechanism
of action of hydroquinone-induced ochronosis.2,6,26,49,50 One
hypothesis is that high levels of hydroquinone inhibit homogen-
tisic acid oxidase enzyme activity in the skin, resulting in
homogentisic acid accumulation, which polymerizes to form
ochronotic pigmentation.51 Another theory is that improper sun
protection in combination with hydroquinone may lead to more
severe exogenous ochronosis. Therefore, sun protection and
sunscreen are recommended for patients using these skin light-
ening agents.26,45,46,47 Furthermore, Findlay et al. hypothesized
that characteristic ochronotic changes in the dermis developed
after the normally disruptive effect on melanocytes was ceased,
thus hydroquinone passed into the dermis where it or its

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8 Review Ochronosis hydroquinone systematic review
metabolites were taken up by fibroblasts that excrete the pig-
ments.6
The safety and efficacy of hydroquinone 4% have been con-
firmed in clinical trials.12,53 For example, in a study of TC cream
for treatment of melasma in 22 female volunteers, the modified
melasma area and severity index decreased significantly from
3.37 to 2.60 at week 4, and to 2.40 at week 8.53 In addition,
skin lightness and severity of pigmentation improved signifi-
cantly after 8 weeks of treatment.53 Side effects included pruri-
tus, scaling, and erythema, primarily experienced during the first
month of application, which were mild and tolerable; ochronosis
was not reported.53 Based on these findings, we conclude that
hydroquinone in concentrations above 4% and in treatment
courses longer than 3 months may be associated with new-
onset ochronosis. Further studies assessing the risk of
hydroquinone-associated ochronosis are thus necessary to
investigate the causal association and control for the confound-
ing factors that may be involved in the pathogenesis of ochrono-
sis in patients using hydroquinone.
Acknowledgement
We thank Paul J Christos Dr.P.H., M.S., for assistance with sta-
tistical analysis.
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