[Downloaded free from http://www.pigmentinternational.com on Wednesday, March 3, 2021, IP: 103.125.48.

53]

Review Article

Diffuse hyperpigmentation: A comprehensive approach

ABSTRACT
Skin color is determined by melanin and other chromophores and is influenced by physical factors (ultraviolet radiation) and other endocrine,
autocrine, and paracrine factors. Being the largest organ of the body, any aberration in skin color (hyperpigmentation and hypopigmentation)
can have impact on the patients’ quality of life. Hyperpigmentation may be circumscribed or diffuse. Diffuse hyperpigmentation can be
multifactorial in origin; hence, a multipronged approach is needed in such cases. First, the cause (systemic or cutaneous) needs to be
ascertained, and then disease-specific management needs to be performed. The biggest challenge in such cases is to treat the
hyperpigmentation itself; hence, counseling and general treatment (the use of broad-spectrum sunscreen, the avoidance of sun exposure,
etc.) play crucial role, and an interdisciplinary approach may be required, especially when the hyperpigmentation is due to a systemic cause.
Keywords: Approach, cause, diffuse hyperpigmentation, investigations, treatment

INTRODUCTION exposure) and facultative (influenced by sun exposure).

Normal skin color is determined mainly by melanin.
Other chromophores such as hemoglobin and carotenoids
also contribute to some extent. Melanocytes are the
melanin-producing cells, originating from the pleuri
potent neural crest cells and distributed in the epidermis,
hair follicle, eye, cochlea, and meninges. They
reside in the interfollicular epidermis and hair
follicle.[1]
Melanocytes are identified by special stains such as
Fontana–Masson, which stain melanin black. Immuno
histochemical techniques using polyclonal antibodies
to specific antigens such as S 100, Melan-A/MART-1,
tyrosinase, and MITF are also used for melanocyte
identification. The major function of melanocytes is
melanin production within its specialized organelles,
melanosomes, which is then transferred to the
surrounding keratinocytes via dendrites. This association
of the melanocytes with the surrounding keratinocytes is
known as “epidermal melanin unit” first described by
Fitzpatrick and Breathnach in 1963.[2,3]
Melanisation is regulated by ultraviolet (UV) irradiation,
as well as endocrine, paracrine, and autocrine
factors. Number, size, shape, and the distribution of
melanosomes lead to racial and ethnic differences in skin
color.
CAUSE
A defect in the process of melanisation either leads
to hypomelanosis or hypermelanosis. Hypermelanosis
is usually due to increased melanin production and
sometimes due to the deposition of drugs or heavy
metals within the dermis. It can be diffuse or
circumscribed. There are numerous causes of diffuse
hyperpigmentation, and it can be classified in many ways.
An etiological classification would simplify the approach to
such cases [Table 1].
ANUPAMA GHOSH, ANUPAM DAS1, RASHMI SARKAR2
CGHS, Kolkata, West Bengal, 1Department of Dermatology, KPC
Medical College and Hospital, Kolkata, West Bengal,
2
Department of Dermatology, MAMC and Associated LNJP
Hospital, New Delhi, India

Two types of melanin pigmentation occur, constitutive Address for correspondence: Dr. Anupam Das, Building −
skin color (genetically determined in the absence of sun “PRERANA,” 19, Phoolbagan, Kolkata 700086, West Bengal, India.
E-mail: anupamdasdr@gmail.com

Access this article online

This is an open access journal, and articles are distributed under the terms of the
Quick Response Code Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows
Website: others to remix, tweak, and build upon the work non-commercially, as long as
www.pigmentinternational.com appropriate credit is given and the new creations are licensed under the identical
terms.

DOI: For reprints contact: reprints@medknow.com

10.4103/Pigmentinternational.
Pigmentinternational_8_17 How to cite this article: Ghosh A, Das A, Sarkar R. Diffuse hyperpigmentation: A
comprehensive approach. Pigment Int 2018;5:4-13.

4 © 2018 Pigment International | Published by Wolters Kluwer - Medknow

[Downloaded free from http://www.pigmentinternational.com on Wednesday, March 3, 2021, IP: 103.125.48.53]

Ghosh, et al.: Approach to diffuse hyperpigmentation

Table 1: Etiological classification of diffuse hyperpigmentation Table 1 (Continued)

(A) Endocrinologic (i) Tanning
(i) Addison’s disease (ii) Lichen planus pigmentosus (LPP) [Figure 5]
(ii) Cushing’s syndrome (iii) Ashy gray dermatosis
(iii) Nelson syndrome (iv) Carbon baby syndrome
(iv) Pheochromocytoma (v) Bronze baby syndrome
(v) Carcinoid (vi) Extensive Mongolian spots
(vi) Acromegaly (vii) Giant melanocytic nevus
(vii) Hyperthyroidism (viii) Adrenoleukodystrophy
(viii) Acanthosis nigricans (ix) Familial progressive hyperpigmentation
(ix) Diabetes (x) Generalized fixed drug rash [Figure 6]
(B) Nutritional (xi) Postinflammatory hyperpigmentation following pemphigus [Figure 7]
(i) Kwashiorkor or erythroderma
(ii) Vitamin B12 deficiency (xii) Idiopathic eruptive macular pigmentation (IEMP)
(iii) Folic acid deficiency (xiii) POEMS syndrome
(iv) Niacin deficiency (xiv) Cronkhite–Canada syndrome
(v) Tryptophan deficiency (xv) Dyschromatosis universalis hereditaria
(vi) Vitamin A deficiency (xvi) Reticulate acropigmentation of Kitamura [Figure 8]
(C) Metabolic
(i) Porphyria cutanea tarda (PCT)
(ii) Hemochromatosis
(iii) Gaucher’s disease
(iv) Niemann–Pick disease
(v) Wilson’s disease
(vi) Chronic renal failure (CRF)
(D) Tumoral
(i) Mycosis fungoides
(E) Physical
(i) Ultraviolet radiation
(ii) Ionizing radiation
(iii) Thermal radiation
(iv) Trauma
(F) Occupational
(i) Pigmented contact dermatitis [Figures 1 and 2]
(ii) Metal deposition in skin – silver, mercury, gold, bismuth, chromates,
copper, and cadmium
(iii) Chemical exposure – arsenic and aromatic hydrocarbons
(G) Medications
(i) Clofazimine [Figure 3]
(ii) Amiodarone
(iii) Minocycline
(iv) Zidovudine [Figure 4]
(v) Antimalarial
(vi) Bleomycin
(vii) Doxorubicin
(viii) Chlorpromazine
(xi) Cyclophosphamide
Figure 1: Pigmented contact dermatitis (Courtesy: Dr. Sumit Sethi,
(x) EGFR inhibitor
Consultant Dermatologist, New Delhi)
(xi) Psoralens
(xii) Imatinib
(xiii) Oral contraceptive pills APPROACH (SUMMARIZED IN THE ALGORITHM)
(H) Deposits – exogenous ochronosis
(I) Autoimmune – systemic sclerosis History
(J) Infections • Onset: disorders that may present since birth include
(i) Onchocerciasis carbon baby syndrome, bronze baby syndrome,
(ii) HIV-associated hyperpigmentation extensive Mongolian spots, and adrenoleukodystrophy.
(K) Miscellaneous
(Continued )
Ashy dermatosis, kwashiorkor, and idiopathic
eruptive macular pigmentation (IEMP) classically
Pigment International | Volume 5 | Issue 1 | January-June 2018 5
[Downloaded free from http://www.pigmentinternational.com on Wednesday, March 3, 2021, IP: 103.125.48.53]
Ghosh, et al.: Approach to diffuse hyperpigmentation
manifest in children. The most common causes
such as lichen planus pigmentosus, endocrinologic
causes, metabolic causes, drugs, malignancy, systemic
sclerosis, POEMS, Cronkhite–Canada syndrome, familial
progressive hyperpigmentation, and occupational
causes are usually manifested in middle-aged patients.
Rarest causes such as malignancy, mycosis fungoides,
and melanoma present in the geriatric age group
[Table 2].
Figure 2: Pigmented contact dermatitis and topical steroid damaged facies
(Courtesy: Dr. Akhilesh Shukla, Consultant Dermatologist, New Delhi)
Table 2: Important past history which serve as diagnostic pointers
(1) Spotting or staining of napkin: alkaptonuria
(2) Fatigue, anorexia, weakness, and weight loss: Addison’s disease,
kwashiorkor, and malignancy
(3) History of weight gain and truncal obesity – acanthosis nigricans and
hypercorticism
(4) High fever and severe joint pain: chikungunya
(5) Jaundice or any liver disease – Wilson’s disease, hemochromatosis, and
porphyria cutanea tarda
(6) Frequent application of any cosmetic or fragrance – pigmented contact
dermatitis (Figures 1 and 2), exochronosis, and Riehl’s melanosis
(7) Drug history should be taken meticulously
(8) History regarding some chronic and sudden onset dermatological
diseases such as atopic dermatitis, photodermatitis, psoriatic
erythroderma, immunobullous diseases (Figure 7), generalized lichen
planus, and Stevens–Johnson syndrome
6 Pigment International | Volume 5 | Issue 1 | January-June 2018
• Sex: the classification of diseases on the basis of gender
predilection is difficult, but adrenoleukodystrophy and
hemochromatosis are more common among males.
Figure 3: Coppery-red pigmentation due to clofazimine in a patient with
leprosy
Table 3: Associated symptoms in systemic causes of diffuse
hyperpigmentation
(a) Raynaud’s disease, dyspnea, tightening of the skin, and esophageal
reflux: systemic sclerosis
(b) Headache, sweating, and palpitation: pheochromocytoma
(c) Weight loss, cachexia, hematemesis, and melena: gastric carcinoma and
thymic carcinoma
(d) Polyuria, polydipsia, polyphagia, dyspnea, and palpitations:
hemochromatosis
(e) Photosensitivity, fluid-filled lesions on sun-exposed areas, and fragility of
the skin: PCT
(f) Chronic liver disease, tremor, gait disturbances, and joint pain: Wilson’s
disease
(g) Easy fatigue, bruise, jaundice, seizures, and ataxia: Gaucher’s disease
(h) Pedal edema and intractable pruritus: CRF
(i) Weight loss, polyuria, polydipsia, polyphagia, burning and tingling
sensation of the hands and feet, and increased skin infection: diabetes
mellitus
(j) Truncal obesity, weight gain, and increased facial hair – hypercorticism
(k) Anorexia, nausea, chronic liver disease, chronic cough, hematuria, and
peripheral neuropathy: chronic arsenicosis
(l) Diarrhea, dementia, seizure, and psychosis – pellagra
(m) Generalized itching, increased pigmentation, and thickness of the skin –
onchocerciasis
(n) Diarrhea, alopecia, and onychodystrophy – Cronkhite–Canada syndrome
(o) Visual disturbances, headache, polyuria, and polydipsia – Nelson syndrome
[Downloaded free from http://www.pigmentinternational.com on Wednesday, March 3, 2021, IP: 103.125.48.53]
Ghosh, et al.: Approach to diffuse hyperpigmentation
However, systemic sclerosis and Nelson syndrome have a
predilection for the opposite sex.
• Residence: the enquiry of residence is crucially
important in patients of chronic arsenicosis because
of the localization of such patients alongside the river
Ganges in West Bengal.
• Course of disease: IEMP, chikungunya, and Gaucher’s
disease have a rapid course of disease.
• Progression: Mongolian spots tend to fade out with age.
However, most of the diseases such as Lichen planus
pigmentosus (LPP), ashy dermatosis, familial progressive
hyperpigmentation, and carbon baby syndrome increase
with age.
• Addiction: the history of addiction is very important,
because it helps to clinch the diagnosis in argyria (usage
of silver-coated mouth fresheners).
• Occupation: the importance of occupational history
cannot be overemphasized. Photography predisposes an
individual to argyria. Jewellery makers are prone to develop
argyria and chrysiasis. Diffuse hyperpigmentation is also
common in factory workers using dye, tar, and chromium,
as well as among coal miners. Besides, agricultural workers
(usage of cotton desiccant, rodenticide, and fungicide), as
well as glass, ceramic, and leather workers, are prone to
develop chronic arsenicosis.
Table 4: Characteristic sites of involvement in diffuse
hyperpigmentation
(1) The preauricular region and temple progressing to the upper extremity,
upper back, and trunk: LPP
(2) Bilaterally symmetrical on the trunk, face, neck, and upper limbs: ashy
gray dermatosis
(3) The face, pinna, and the tip of nose: chikungunya
(4) The lower back and buttocks: Mongolian spots
(5) The acral regions (the dorsum of hands, feet, fingers, and toes) and
digit joints with sparing of the nail beds: vitamin B12 deficiency
(6) Flexures or pressure points – kwashiorkor
(7) Sun-exposed parts of the body with additional features: PCT
(8) Generalized hyperpigmentation sparing the palms and soles –
adrenoleukodystrophy
(9) Axial distribution and usually >20 cm – giant melanocytic nevus
(10) Multiple hyperpigmented macules and plaques over the face, trunk,
and upper extremities – idiopathic eruptive macular pigmentation
(11) Generalized with involvement of the mucous membrane, palms, and
soles – dyschromatosis universalis hereditaria
(12) Sun-exposed parts to generalised involvement: hemochromatosis
(13) The ear cartilage, axillae, sclera, and conjunctiva: alkaptonuria
(14) Symmetrical hyperpigmented velvety plaques over the neck, axillae,
groin, knuckles, and oral and genital mucosa – acanthosis nigricans
(15) Round, hyperpigmented depressed lesions on the shin – diabetes
mellitus
(16) Frictional areas, shear stress, nipple, areola, palmar crease, scars, and
sun-exposed sites: Addison’s disease
(17) Lower extremities and finger nails: Wilson’s disease
(18) Linea nigra and hyperpigmentation of the scars, gingiva, scrotum, and
areola – Nelson syndrome
Pigment International | Volume 5 | Issue 1 | January-June 2018
• Past history: this provides significant diagnostic
pointers in the cases of hyperpigmentation [Table 3].
In cases of hyperpigmentation associated with
underlying systemic disorders, we must meticulously
enquire about the associated symptoms [Table 4].
• Family history: it is contributory in cases of
hemochromatosis, Wilson’s disease, alkaptonuria,
Gaucher’s disease, Niemann–Pick disease, POEMS
syndrome, chronic arsenicosis, familial progressive
hyperpigmentation, diabetes mellitus, extensive
Mongolian spots in mucopolysaccharidoses, and
porphyria cutanea tarda.
Clinical examination
After taking history, the patient has to be examined. First,
a general examination of the patient has to be performed
to assess the general health of the patient followed
by detailed mucocutaneous examination and systemic
examination.
Table 5: Color of the pigment in diffuse hyperpigmentation
(1) Dark-brown to grayish: LPP
(2) Bluish-gray: ashy gray dermatosis
(3) Bluish-black: alkaptonuria and minocycline
(4) Bronze discoloration: hemochromatosis
(5) Brown: Wilson’s disease and CRF
(6) Yellow-brown: Niemann–Pick disease
(7) Slate-gray: amiodarone
(8) Coppery-red: clofazimine
(9) Deep brown: vitamin B12 deficiency
(10) Jet black: carbon baby syndrome
Table 6: Associated cutaneous findings in diffuse
hyperpigmentation
(a) Papules, nodules, cafe au lait macules, Mongolian spots, xanthomas,
and xanthogranulomas: Niemann–Pick disease
(b) Keratotic pits on the palms and soles, keratoderma, rain drop
pigmentation, Bowen’s disease, squamous cell carcinoma, and basal cell
carcinoma: chronic arsenicosis
(c) Casal’s necklace, photosensitivity, erythema, and dry crackled skin:
pellagra
(d) Dry, dark skin with flaky paint dermatosis – kwashiorkor
(e) Pigmented linea alba, scars, and chloasma: pregnancy
(f) Acne, skin tags, hypertrichosis, cutis verticis gyrata, and acanthosis
nigricans: acromegaly
(g) Acne, hirsutism, striae distensae, and telangiectasia: hypercorticism
(h) Palmar and facial erythema, pruritus, pretibial myxedema, alopecia
areata, vitiligo, Plummer’s nails, and Jellinek’s sign: hyperthyroidism
(i) Skin fragility, milia, scarring, mottled pigmentation, and sclerodermoid
changes: PCT
(j) Azure lunula, Kayser–Fleischer ring, spider angioma, and palmar
erythema: Wilson’s disease
(k) Vitiligo and decreased pubic and axillary hair – Addison’s disease
(l) Multiple skin tags – acanthosis nigricans
(m) Necrobiosis lipoidica diabeticorum and foot ulcer – diabetes mellitus
7
[Downloaded free from http://www.pigmentinternational.com on Wednesday, March 3, 2021, IP: 103.125.48.53]
Ghosh, et al.: Approach to diffuse hyperpigmentation
General examination
Altered mental status and clubbing is found in patients
with Wilson’s disease. Pallor is a feature in those with
chronic renal failure (CRF), Gaucher’s disease, and
Niemann–Pick disease, whereas icterus accompanies
Wilson’s disease and hemochromatosis. Pedal edema is
an important finding in patients with CRF, kwashiorkor,
POEMS, and hyperthyroidism. Pulse rate often gives
Figure 4: Generalized pigmentation due to zidovudine in a patient
receiving highly active anti-retroviral therapy (HAART) (Courtesy: Dr.
Mahimanjan Saha, Senior Resident, Dermatology, Gouri Devi Institute
of Medical Sciences, Durgapur)
Figure 5: Bluish-gray pigmentation in lichen planus pigmentosus
8 Pigment International | Volume 5 | Issue 1 | January-June 2018
important clues for diagnosis. Tachycardia is found in
those with Cushing’s syndrome, pheochromocytoma,
carcinoid syndrome, and hyperthyroidism. However,
bradycardia is a feature of Addison’s disease.
Hypertension is a vital pointer toward Cushing’s
syndrome, pheochromocytoma, CRF, systemic sclerosis, etc.
Cutaneous examination
(1) Site of involvement: in patients with diffuse hyper-
pigmentation, thorough examination to determine
the site of the onset of pigmentation and areas
with more intense pigmentation gives important
clues toward the diagnosis. This is summarized in
Table 5.
(2) Color of pigmentation: differentiating the causes
of pigmentation on the basis of the color of the
pigment is difficult in Indian skin; however,
knowledge of the typical color is important in frank
cases so that the diagnosis is not missed
[Table 6].
(3) Additional cutaneous lesions: in most of the patients,
there are numerous accompanying lesions, which help
us arriving at a diagnosis [Table 7].
(4) Examination of the nails: longitudinal melanonychia is
a finding in pregnancy, alkaptonuria, deficiency
disorders, porphyria, and human immunodeficiency
virus infection. Muehrcke lines and Terry nails are
typical of CRF. Mee’s lines are classically found in
cases of chronic arsenicosis. Azure lunulae are found
in those with Wilson’s disease. White superficial
onychomycosis is a pathognomonic sign of HIV
infection.
(5) Examination of the mucosae: hyperpigmentation
of the oral mucosa is found in patients with Addison’s
disease, Nelson syndrome, chronic arsenicosis,
[Downloaded free from http://www.pigmentinternational.com on Wednesday, March 3, 2021, IP: 103.125.48.53]

Ghosh, et al.: Approach to diffuse hyperpigmentation

familial progressive hyperpigmentation, and argyria.
Glossitis and angular cheilitis are found in patients with
vitamin B12 deficiency and pellagra. Angular stomatitis
and atrophy of the papilla are features of kwashiorkor
disease. Oral and/or genital mucosa may be involved in
acanthosis nigricans associated with an underlying
malignancy.
(6) Examination of the hair: dry, lusterless, easily pluckable,
unruly hair with flag sign is a classical finding in patients
with kwashiorkor. Premature canities may be present in
patients with vitamin B12 deficiency.

Table 7: Classification of causes of hyperpigmentation on the

basis of histopathology
Group A: increased epidermal melanin
Increased number of melanocytes: UV radiation and photochemotherapy
treatment
Normal number of melanocytes: pregnancy, hyperthyroidism and
Gaucher’s type I disease (adult)
Group B: increased epidermal and dermal melanin
Endocrinologic
Nutritional deficiencies
Universal acquired melanosis
Autoimmune
Medication-induced
Liver disease: primary biliary cirrhosis
Malignancy: mycosis fungoides
Metabolic: PCT
Group C: increased melanin within macrophages
Phototoxic/photoallergic drug reactions
Generalized melanosis of metastatic melanoma
Storage disease: Niemann–Pick type A disease
Group D: pigmentation due to non-melanin chromogens
Histologically undetectable: bilirubin, biliverdin, carotenoids, and mixed
Normal epidermal melanin: iron, heavy metals, and clofazimine
Increased epidermal melanin: silver and arsenic
Figure 6: Generalized fixed drug rash

Figure 7: Postinflammatory hyperpigmentation following pemphigus vulgaris (Courtesy: Dr Komal Agarwal, Junior Resident, Dermatology, Assam
Medical College, Dibrugarh)

Pigment International | Volume 5 | Issue 1 | January-June 2018 9

[Downloaded free from http://www.pigmentinternational.com on Wednesday, March 3, 2021, IP: 103.125.48.53]

Ghosh, et al.: Approach to diffuse hyperpigmentation

Systemic examination
This supplements our findings of cutaneous exami-
nation, and in many cases, we may come across
important findings that help us associate them with
the dermatological lesions, for example, hepatomegaly
is a feature of hemochromatosis, porphyria cutanea
tarda, Wilson’s disease, chronic arsenicosis, and
kwashiorkor. Similarly, neurologic examination is vital
in cases of Wilson’s disease, vitamin B12 deficiency,
and pellagra.
Investigations
Investigations help to arrive at a final diagnosis. General
investigations are first conducted to evaluate the general
health of the patient and rule out any contraindications to
treatment. This is followed by specific investigations to
confirm the cause.
General investigations
(1) Complete hemogram: megaloblastic anemia in
patients with vitamin B12 deficiency; anemia
and thrombocytopenia those with in Gaucher’s
disease; lymphopenia in patients with chikun-
gunya, etc.
(2) Liver function test: deranged liver in patients with
porphyria cutanea tarda, hemochromatosis, Wilson’s
disease, and Gaucher’s disease.
(3) Blood sugar.

Table 8: Algorithmic approach to diffuse hyperpigmentation

History
Onset of pigmentation : Since birth/ childhood/ middle age/ elderly
Course of disease : Rapid/ slow
Gender and residence of the patient : Clues in genetic disorders, arsenicosis
Progression of disease : Self-limiting/ progressive
Occupation : Exposure to silver, gold, tars, dyes, coalmines

Salient features in general examination and systemic survey

Mental status
Clubbing
Pallor
Icterus
Pedal edema
Hypertension

Cutaneous examination
Site : Head and neck/ flexures/ photo-exposed areas
Color : Brown/ blue/ black/ grey/ combination
Additional lesions
Nails, mucosae and hairs

General investigations
Complete hemogram
Liver function test
Renal function test
Blood sugar
Thyroid profile
Serum Vitamin B12 estimation
Radiological survey

Specific investigations
Woods lamp : To find out whether pigment is epidermal/ dermal/ mixed
Histopathology : To find out the nature and location of pigment; number of melanocytes

Treatment of the underlying condition

10 Pigment International | Volume 5 | Issue 1 | January-June 2018

[Downloaded free from http://www.pigmentinternational.com on Wednesday, March 3, 2021, IP: 103.125.48.53]

Ghosh, et al.: Approach to diffuse hyperpigmentation

(4) T3, T4, and TSH. Specific investigations

(5) Arsenic levels in water, the hair, and the nails. (1) Wood’s lamp: reveals whether the pigmentation is
(6) Serum vitamin B12 estimation. epidermal, dermal, or mixed.
(7) Ultrasonography of the abdomen – in (2) Histopathology: it is the most conclusive investigation,
patients with Wilson’s disease or hemo- and findings can be classified into three groups[4] on
chromatosis. the basis of the following:
(8) Computed tomography scan – acanthosis nigricans due (a) Nature of pigment (melanin, non-melanin, mixed,
to malignancy. or undetermined).
(b) Localization of pigment (epidermal or dermal).
Table 9: Treatment of conditions causing diffuse hyperpigmentation
(c) Concomitant increase in the number of
melanocytes (present or absent).
Disease Treatment
Lichen planus Photoprotection
On the basis of the histological findings, the diseases can be
pigmentosus[5-9]
Topical: steroid, tacrolimus classified into four groups[4] [Table 8].
Systemic: steroid, vitamin A, dapsone, colchicine,
and hydroxychloroquine Few representative photomicrographs have been provided
Porphyria cutanea Photoprotection [Figures 9–11].
tarda[10-12]
Avoiding alcohol, hepatotoxic drugs, estrogen
therapy, and excess iron supplements Treatment
Phlebotomy Treatment is mostly cause specific, but some general
Low-dose antimalarials measures such as photoprotection (avoidance of
Iron chelating agents sun exposure and the use of broad-spectrum
sunscreens) and the avoidance of known triggers
Alkaptonuria[13] Avoidance of products containing tyrosine and
always help. Counseling is an integral part of the
phenylalanine
High doses of vitamin C
therapy, because many conditions are difficult to cure.
Nonsteroidal anti-inflammatory drugs The management of some the diseases has been
Physiotherapy summarized in Table 9.
Addison’s disease Replacement of mineralocorticoids and
glucocorticoids
CONCLUSION
Acromegaly Surgery of pituitary adenomas
Somatostatin analogues
Dopamine analogues Diffuse hyperpigmentation is not a disease per se; rather,
Growth hormone receptor antagonist it is a presentation of numerous conditions. We have
(pegvisomant) provided a comprehensive approach regarding the same.
Vitamin B12 Intramuscular B12 1 mg per week for 1 month The onset of diffuse pigmentation may be at birth or
deficiency followed by 1 mg per month till reversal
during childhood. However, the most common causes
Pellagra Oral nicotinamide 100 mg thrice daily till reversal
Acanthosis Weight reduction
have an onset during middle age. Most of the
nigricans[14-24] diseases have a tendency to progress with age.
Topical: retinoids, calcipotriol, and ammonium General examination and systemic survey hold crucial
lactate importance when the cause of the pigmentation is an
Systemic: retinoid, metformin, rosiglitazone, and
underlying systemic disease. The clinical diagnosis is
glimepiride
Trichloroacetic peels clear in most of the cases with the help of a
Long-pulsed alexandrite lasers proper cutaneous examination with special reference
Argyria[25] Avoidance of the causative agents to the site and color of the pigmentation. Besides,
Q-switched frequency doubled Nd–Yag laser associated cutaneous findings and an examination
Gaucher’s disease Enzyme replacement therapy with recombinant of the mucosae, hairs, and nails give important
[26-29]
acid β-glucosidase
diagnostic clues. Depending on the differential
Substrate reduction therapy (SRT) with eliglustat
Systemic sclerosis Topical: steroid, calcipotriol, and retinoid
diagnoses, relevant blood investigations and biopsy
Pigmented contact Avoidance of the allergen for histopathology may be warranted. The treatment of
dermatitis[30,31] the presentation is mainly directed toward photo-
Topical: steroid, hydroquinone, and tretinoin protection, topical steroids, calcineurin inhibitors,
Glycolic acid peels systemic agents, and the management of the
Drug induced No treatment required (condition is reversible)
underlying disease.
Pigment International | Volume 5 | Issue 1 | January-June 2018 11
[Downloaded free from http://www.pigmentinternational.com on Wednesday, March 3, 2021, IP: 103.125.48.53]

Ghosh, et al.: Approach to diffuse hyperpigmentation

Figure 8: Generalized hyperpigmentation with palmar pits in reticulate acropigmentation of Kitamura

Figure 9: Photomicrograph showing increased melanisation of the basal

layer in a case of postinflammatory hyperpigmentation (hematoxylin and
eosin, 100×)
Figure 11: Photomicrograph showing a hyperpigmented basal layer, a
collection of the neutrophils and lymphocytes in the dermis in a patient
with lepra reaction during multi-drug therapy (MDT) for leprosy
(hematoxylin and eosin, 100×)

given his/her/their consent for his/her/their images and

other clinical information to be reported in the journal.
The patients understand that their names and initials will
not be published and due efforts will be made to conceal
their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.
Figure 10: Photomicrograph showing basal layer degeneration, a band-
like infiltrate of the lymphocytes, increased melanisation of the basal Conflicts of interest
layer, and pigment incontinence in a case of generalized lichen planus
There are no conflicts of interest.
(hematoxylin and eosin, 40×)

REFERENCES
Declaration of patient consent
The authors certify that they have obtained all appropriate 1. Tobin DJ, Bystryn JC. Different populations of melanocytes are present
patient consent forms. In the form the patient(s) has/have in hair follicles and epidermis. Pigment Cell Res 1996;9:304-10.

12 Pigment International | Volume 5 | Issue 1 | January-June 2018

[Downloaded free from http://www.pigmentinternational.com on Wednesday, March 3, 2021, IP: 103.125.48.53]
Ghosh, et al.: Approach to diffuse hyperpigmentation
2. Fitzpatrick TB, Breathnach AS. Das epidermale melamim-einheit
system. Dermatol Wochenschr 1963;147:481-9.
3. Hadley ME, Quevedo WC. Vertebrate epidermal melanin unit. Nature
1966;209:1334-5.
4. Stefanato CM, Bhawan J. Diffuse hyperpigmentation of the skin: A
clinicopathologic approach to diagnosis. Semin Cutan Med Surg
1997;16:61-71.
5. Bhutani LK, Bedi TR, Pandhi RK, Nayak NC. Lichen planus
pigmentosus. Dermatologica 1974;149:43-50.
6. Sehgal VN, Verma P, Bhattacharya SN, Sharma S, Rasool F. Lichen
planus pigmentosus. Skinmed 2013;11:96-103.
7. Al-Mutairi N, El-Khalawany M. Clinicopathological characteristics of
lichen planus pigmentosus and its response to tacrolimus ointment: An
open label, non-randomized, prospective study. J Eur Acad Dermatol
Venereol 2010;24:535-40.
8. Bhutani LK, George M, Bhate SM. Vitamin A in the treatment of lichen
planus pigmentosus. Br J Dermatol 1979;100:473-4.
9. Ghosh A, Coondoo A. Lichen planus pigmentosus: The controversial
consensus. Indian J Dermatol 2016;61:482-6.
10. Christiansen AL, Aagaard L, Krag A, Rasmussen LM, Bygum A.
Cutaneous porphyrias: Causes, symptoms, treatments and the Danish
incidence 1989–2013. Acta Derm Venereol 2016;96:868-72. doi:
10.2340/00015555-2444.
11. Tintle S, Alikhan A, Horner ME, Hands JL, Davis DM. Cutaneous
porphyrias. Part II: Treatment strategies. Int J Dermatol 2014;
53:3-24.
12. Singal AK, Kormos-Hallberg C, Lee C, Sadagoparamanujam VM,
Grady JJ, Freeman DH Jr, et al. Low-dose hydroxychloroquine is as
effective as phlebotomy in treatment of patients with porphyria cutanea
tarda. Clin Gastroenterol Hepatol 2012;10:1402-9.
13. Cieszyński K, Podgórny J, Mostowska A, Jagodziński PP,
Grzegorzewska AE. Alkaptonuria: A disease with dark brown urine.
Pol Arch Med Wewn 2016;126:284-5.
14. Bellot-Rojas P, Posadas-Sanchez R, Caracas-Portilla N, Zamora-
Gonzalez J, Cardoso-Saldaña G, Jurado-Santacruz F, et al.
Comparison of metformin versus rosiglitazone in patients with
acanthosis nigricans: A pilot study. J Drugs Dermatol 2006;5:884-9.
15. Jeong JS, Lee JY, Yoon TY. Unilateral nevoid acanthosis nigricans
with a submammary location. Ann Dermatol 2011;23:95-7.
16. Lahiri K, Malakar S. Topical tretinoin in acanthosis nigricans. Indian J
Dermatol Venereol Leprol 1996;62:159-61.
Pigment International | Volume 5 | Issue 1 | January-June 2018
17. Higgins SP, Freemark M, Prose NS. Acanthosis nigricans: A practical
approach to evaluation and management. Dermatol Online J 2008;14:2.
18. Kapoor S. Diagnosis and treatment of acanthosis nigricans. Skinmed
2010;8:161-4.
19. Phiske MM. An approach to acanthosis nigricans. Indian Dermatol
Online J 2014;5:239-49.
20. Hermanns-Lê T, Scheen A, Piérard GE. Acanthosis nigricans associated
with insulin resistance: Pathophysiology and management. Am J Clin
Dermatol 2004;5:199-203.
21. Atabek ME, Pirgon O. Use of metformin in obese adolescents with
hyperinsulinemia: A 6-month, randomized, double-blind, placebo-
controlled clinical trial. J Pediatr Endocrinol Metab 2008;21:339-48.
22. Tankova T, Koev D, Dakovska L, Kirilov G. Therapeutic approach in
insulin resistance with acanthosis nigricans. Int J Clin Pract 2002;56:
578-81.
23. Bermúdez-Pirela VJ, Cano C, Medina MT, Souki A, Lemus MA, Leal
EM, et al. Metformin plus low-dose glimeperide significantly improves
Homeostasis Model Assessment for insulin resistance (HOMA (IR)) and
beta-cell function (HOMA (beta-cell)) without hyperinsulinemia in
patients with type 2 diabetes mellitus. Am J Ther 2007;14:194-202.
24. Rosenbach A, Ram R. Treatment of acanthosis nigricans of the axillae
using a long-pulsed (5-msec) alexandrite laser. Dermatol Surg 2004;30:
1158-60.
25. Rhee DY, Chang SE, Lee MW, Choi JH, Moon KC, Koh JK. Treatment
of argyria after colloidal silver ingestion using Q-switched 1,064-nm
Nd:YAG laser. Dermatol Surg 2008;34:1427-30.
26. Chen M, Wang J. Gaucher disease: Review of the literature. Arch
Pathol Lab Med 2008;132:851-3.
27. Grabowski GA. Phenotype, diagnosis, and treatment of Gaucher’s
disease. Lancet 2008;372:1263-71.
28. Kaplan P, Baris H, De Meirleir L, Di Rocco M, El-Beshlawy A,
Huemer M, et al. Revised recommendations for the management of
Gaucher disease in children. Eur J Pediatr 2013;172:447-58.
29. Shayman JA. Eliglustat tartrate: Glucosylceramide synthase inhibitor
treatment of type 1 Gaucher disease. Drugs Future 2010;35:613-20.
30. Shenoi SD, Rao R. Pigmented contact dermatitis. Indian J Dermatol
Venereol Leprol 2007;73:285-7.
31. Vasudevan B, Verma R, Venugopal R. Pigmented variants of skin
disorders. In: Lahiri K, Chatterjee M, Sarkar R, editors. Pigmentary
Disorders A Comprehensive Compendium. 1st ed. New Delhi: Jaypee
Brothers Medical Publishers (P) Ltd.; 2014. p. 125-6.
13