Pigment International
t 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....
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INTRODUCTION

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 pleuripotent 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. Immunohistochemical 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.[23]

Two types of melanin pigmentation occur, constitutive skin color (genetically determined in the absence of sun exposure) and facultative (influenced by sun exposure). 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].

APPROACH (SUMMARIZED IN THE ALGORITHM)

History

Onset: disorders that may present since birth include carbon baby syndrome, bronze baby syndrome, extensive Mongolian spots, and adrenoleukodystrophy. Ashy dermatosis, kwashiorkor, and idiopathic eruptive macular pigmentation (IEMP) classically 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].

Sex: the classification of diseases on the basis of gender predilection is difficult, but adrenoleukodystrophy and hemochromatosis are more common among males. 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.

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.

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 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

Site of involvement: in patients with diffuse hyperpigmentation, 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.

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].

Additional cutaneous lesions: in most of the patients, there are numerous accompanying lesions, which help us arriving at a diagnosis [Table 7].

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.

Examination of the mucosae: hyperpigmentation of the oral mucosa is found in patients with Addison's disease, Nelson syndrome, chronic arsenicosis, 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.

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.

Systemic examination

This supplements our findings of cutaneous examination, 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

Complete hemogram: megaloblastic anemia in patients with vitamin B12 deficiency; anemia and thrombocytopenia those with in Gaucher's disease; lymphopenia in patients with chikungunya, etc.

Liver function test: deranged liver in patients with porphyria cutanea tarda, hemochromatosis, Wilson's disease, and Gaucher's disease.

Blood sugar.

T3, T4, and TSH.

Arsenic levels in water, the hair, and the nails.

Serum vitamin B12 estimation.

Ultrasonography of the abdomen – in patients with Wilson's disease or hemochromatosis.

Computed tomography scan – acanthosis nigricans due to malignancy.

Specific investigations

Wood's lamp: reveals whether the pigmentation is epidermal, dermal, or mixed.

Histopathology: it is the most conclusive investigation, and findings can be classified into three groups[4] on the basis of the following:

Nature of pigment (melanin, non-melanin, mixed, or undetermined).

Localization of pigment (epidermal or dermal).

Concomitant increase in the number of melanocytes (present or absent).

On the basis of the histological findings, the diseases can be classified into four groups[4] [Table 8].

Few representative photomicrographs have been provided [Figures 91011].

Treatment

Treatment is mostly cause specific, but some general measures such as photoprotection (avoidance of sun exposure and the use of broad-spectrum sunscreens) and the avoidance of known triggers always help. Counseling is an integral part of the therapy, because many conditions are difficult to cure. The management of some the diseases has been summarized in Table 9.

CONCLUSION

Diffuse hyperpigmentation is not a disease per se; rather, it is a presentation of numerous conditions. We have provided a comprehensive approach regarding the same. The onset of diffuse pigmentation may be at birth or during childhood. However, the most common causes have an onset during middle age. Most of the diseases have a tendency to progress with age. General examination and systemic survey hold crucial importance when the cause of the pigmentation is an underlying systemic disease. The clinical diagnosis is clear in most of the cases with the help of a proper cutaneous examination with special reference to the site and color of the pigmentation. Besides, associated cutaneous findings and an examination of the mucosae, hairs, and nails give important diagnostic clues. Depending on the differential diagnoses, relevant blood investigations and biopsy for histopathology may be warranted. The treatment of the presentation is mainly directed toward photoprotection, topical steroids, calcineurin inhibitors, systemic agents, and the management of the underlying disease.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have 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.[31]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.