Addisonian Pigmentation – The Great Mimicker – A Review

Abstract

Skin colour usually depends upon melanin, haemoglobin, and carotenoids. Pigmentary disorders indicate an increased amount of melanin, leading to a darker colour of the skin, called hypermelanosis. Addison’s disease is a rare endocrinal disorder with severe oral and systemic manifestations. Any form of diffuse skin hyper-pigmentation which is more pronounced on sun-exposed areas mimics Addison’s disease and is called Addisonian pigmentation. Pigmentation often precedes other manifestations by months to years and hence can lead to early diagnosis and can prevent life-threatening adrenal crisis. The most common cause of adrenal insufficiency in developing countries is tuberculosis. A similar pattern of pigmentation has been reported in Cushing’s syndrome, ectopic ACTH-producing tumours, vitamin B12 deficiency, and thyrotoxicosis. Addisonian pigmentation can be a manifestation of multiple systemic diseases; hence, an inter-disciplinary approach is needed with extensive clinical and laboratory evaluation. It is not merely a cosmetic concern. Not much data are available in the literature regarding this entity. This brief review serves as an important source for clinicians to stay up-to-date regarding the history, clinical presentation, differential diagnosis, and management of this entity.

Introduction

Normal skin colour depends mainly on melanin, haemoglobin (oxidized and reduced), and carotenoids. Melanin is the primary chromophore that determines the colour of the skin. Melanin is produced by epidermal melanocytes which are derived embryonically from neural crest cells that migrate into the basal layer of the epidermis. Melanin through melanosomes is transferred to the surrounding keratinocytes, giving the skin its colour. Pigmentary disorders typically indicate an increased amount of melanin, leading to a darker colour of the skin, called hypermelanosis or hyper-pigmentation. The melanocytes interact with intrinsic factors such as endocrine, immunity, and inflammatory factors. Melanogenesis is also regulated by extrinsic factors such as ultraviolet radiation and drugs.[1]

Addison’s Disease

Addison’s disease is a rare endocrinal disorder that affects 1 in 10,000 people with several oral and systemic manifestations. It is seen in all age groups and affects male and female equally. It is an acquired primary adrenal insufficiency, which is termed Addison disease when an auto-immune process causes the condition.[2] It results from destruction of the bilateral adrenal cortex, leading to decreased adrenocortical hormones (cortisol, aldosterone, and androgens). Although its insidious course of action usually presents with glucocorticoid deficiency followed by mineralocorticoid, it can present acutely, often triggered by inter-current illness. Adrenal insufficiency is classified as primary or secondary [Tables 1 and 2].

Table 1.

Causes of Addison’s disease

Primary adrenal insufficiency	Secondary insufficiency
Infections (tuberculosis, HIV, and other infectious causes including disseminated fungal infections, histoplasmosis, and syphilis)	Due to exogenous steroid administration resulting in suppression of ACTH synthesis, which results in ultimately reduction of glucocorticoid production.
Auto-immune disorders (can be part of auto-immune polyglandular endocrinopathy)
Sarcoidosis, lymphoma, and
genetic disorders such as congenital adrenal hyperplasia and adrenal leukodystrophy

Table 2.

Clinical presentation and laboratory investigation findings of Addison’s disease

Clinical presentation	Laboratory investigation findings
Muscle weakness and fatigue	Hypoglycaemia
Hyper-pigmentation Nausea, diarrhoea, or vomiting	hyponatremia
Weight loss and decreased appetite	Hyperkalaemia
Muscle or joint pains	Eosinophilia
Salt craving	Lymphocytosis
Changes in mood and personality	Low blood pressure
Depression	-
Weakness	-
Dehydration	-
Headache	-
Sweating	-

Primary adrenal insufficiency is caused by direct injury to the adrenal cortex. Among infections, tuberculosis accounts for 20–30% of Addison’s disease and is associated with bilateral adrenal gland involvement. Adrenal tuberculosis is seen in 6% of patients with active tuberculosis.[3] Although the basis of Addison’s disease has dramatically changed from an infectious cause to auto-immune pathology since its initial description, tuberculosis is still the predominant cause of Addison’s disease in developing countries. Vijayalakshmi L[3] reported a case of 15-year-old boy who presented with progressive hyper-pigmentation of the face, trunk, and extremities, which was more accentuated over the sun-exposed area along with pigmentation of the nail and mucosa. Routine laboratory investigations were normal. His serum electrolytes showed hyponatremia and hyperkalaemia with evidence of hypocortisolemia and increased serum ACTH. Chest X-ray was suggestive of pulmonary tuberculosis; sputum AFB was positive, and Mantoux was strongly positive. Primary adrenal insufficiency was confirmed, and ATT was initiated along with steroid replacement therapy. Addison’s disease caused by tuberculosis can also present with atypical hyper-pigmentation, as was noted by Namikawa H et al.,[4] a 48-year-old man. He presented with exacerbation of the pigmentation of freckles and the occurrence of new freckles. He was diagnosed with Addison’s disease caused by tuberculosis, and his clinical condition was markedly ameliorated by the administration of hydrocortisone and anti-tuberculosis agents. We had a 38-year-old female patient who presented with diffuse hyper-pigmentation over the face and exposed part of the body, and later on, she was diagnosed with pulmonary tuberculosis with primary adrenal insufficiency. Currently, she is on glucocorticoid and mineralocorticoid replacement therapy and anti-tubercular therapy [Figures 1-3].

Figure 1.

A 35-year-old female with diffuse pigmentation seen over the face (a) and neck (b)

Figure 3.

Dark-brown macules present over the buccal mucosa (a) and hard palate (b). Her CECT abdomen showed bilateral enlargement of the adrenal gland (larger and mass like on the left side) showing heterogeneous enhancement with a necrotic centre and peripheral enhancing rims suggestive of necrotic deposits involving bilateral adrenal glands – infective tuberculosis, histoplasmosis (c)

Figure 2.

Accentuation of pigmentation over the palmer creases (a) and pigmentation present over the knuckles on dorsal surface of the hands (b)

Addisonian pigmentation

Due to destruction of the adrenal cortex, there is interruption of feedback inhibition of the hypothalamus and anterior pituitary. MSH is concurrently released and stimulates the enzyme tyrosinase in melanocytes, resulting in pigmentation of the skin and mucosa, which is one of the most important manifestations of Addison disease. Generalized cutaneous and mucosal pigmentation related to the ACTH melanogenesis action is the hallmark of Addison disease. It often precedes other manifestations by months to years, and it occurs when 90% of the adrenal gland is destroyed. Any form of diffuse pigmentation more pronounced on sun-exposed areas may mimic Addison’s disease and is called Addisonian pigmentation. The onset of pigmentation may be insidious, and it is epidermal melanotic hyper-pigmentation.[3]

Pigmentation can be brownish black, homogeneous, or blotchy and may involve the skin, oral cavity, conjunctiva, and genitalia. It is also called as bronze pigmentation. It does not depend on the gender or race. It is observed in almost all adult patients and 67% of paediatric patients. Pigmentation in some children may be quite diffuse, and comparison of children to other family members may be useful in ascertaining clinical findings.[5] It is most pronounced on the sun-exposed areas, areas subjected to repeated frictions (perineum, groin, and axilla), elbows and knuckles, palmer and plantar creases, and recently acquired scars and nevi. It involves the dorsum of hands and feet with periungual accentuation. Palmoplantar involvement can vary from patchy to diffuse brownish discolouration. Mucosal pigmentation is one of the most important features. Brown patches of the gingival, vermillion border of the lips, buccal mucosa, palate, and tongue may represent the first signs of Addison’s disease.[6] New pigmented nevi may appear. The hair becomes more pigmented. There may be a loss of axillary and pubic hair, which are dependent on adrenal production. The nail may show diffuse pigmentation, longitudinal melanonychia, or pigmentation of the onychodermal band.[7] Longitudinal melanonychia can be the first and only manifestation of Addison’s disease as reported by Prat et al.[8] in a 65-year-old female who presented with a 4-year history of nail pigmentation and was diagnosed with Addison’s disease on further evaluation. Hence, Addison’s disease should be included in the differential diagnosis of longitudinal melanonychia as it can lead to early diagnosis of the disease and avoid life-threatening complications.

A similar pattern of pigmentation has been reported in a lot of endocrinological conditions, nutritional diseases, and auto-immune diseases [Table 3]. Drugs and medications constitute to about 10–20% of all cases of acquired pigmentation [Table 4]. Although no significant differences have been noted between gender, age, and racial groups, individuals with a darker skin may display more severe hyper-pigmentation.

Table 3.

Differential diagnosis of Addisonian pigmentation

Dermatological conditions	Clinical features
Endocrinological conditions	Addison’s disease: Diffuse pigmentation over the sun-exposed area and the area of repeated friction.
	Mucosal involvement is common, can precede other features by months to years.
	Cushing’s syndrome: There will be Cushingoid manifestations along with Addisonian pigmentation.
	Nelson syndrome: Associated neuro-opthalmic symptoms can be present along with Addisonian pigmentation.
	Thyrotoxicosis: Less involvement of mucosa, nipples, genital skin, and poor response of the reversibility of pigmentation with treatment.
Nutritional diseases	Vitamin B12 deficiency: More common in darker-skinned individuals. Can present with vitiligo, hair changes, and recurrent angular stomatitis also along with pigmentation over friction prone areas, extremities, and mucosa.
	Can have a range of haemtologic, psychiatric, and neurological manifestations also.
	Folic acid deficiency: A diffuse brown pigmentation similar to vitamin B12 deficiency.
	Pellagra: Affected skin (sun-exposed) becomes dry, hard, cracked, and in extreme cases black in colour. Mucosa involved.
	Vitamin A deficiency: Hyper-pigmentation of the face and limbs in children. Xerosis, scaling of the skin with desquamation, and generalised hyper-pigmentation in adults. Conjunctival pigmentation has been noted.
	Xerophthalmia and phrynoderma can be seen
Drugs	Amiodarone, cytotoxic drugs, anti-malarials, phenytoin, psychotropic drugs, and teytacyclines [Table 3]
Auto-immune diseases*	Systemic sclerosis: Diffuse generalised pigmentation especially in dark-skinned individuals. Mucosa not involved. Salt and pepper pigmentation usually seen.
	SLE: Diffuse pigmentation of the sun-exposed area present that may gradually develop even after disease is controlled by treatment. Longitudinal melanonychia may be seen. and Dermatomyosistis, facial hyper-pigmentation, can be seen, which can be a sign of relapse also. Quite common in dark-skinned individuals. Can be present along with dyspigmentation.
Other systemic diseases*	Multiple organ failure and renal failure: Failure of kidneys leads to slow clearance and deposition of melanin, lipochromes, and carotenoids.
	Neoplastic and paraneoplastic syndrome: Due to excessive production of MSH and ACTH by the tumours.
	Haemochromatosis: Diffuse bronze pigmentation seen. Mucosa and conjunctivae involvement seen in 15–20% cases.
	Neurological disorders: Schilder disease, hepatocellular degeneration, chronic schizophrenias, post-encephalitic Parkinsonism, and period of intense stress.
Miscellaneous*	(a) Syndromic:
	• POEMS: Hyper-pigmentation mainly affecting extremities, torso, areolae, head, and neck.
	• Crohnkite Canada syndrome: Other features also seen – gastrointestinal polyp, cutaneous pigmentation, alopoecia, and onychodystrophy.
	(b) Non-melanin pigmentary disorders:
	• Argyria: Slate grey pigmentation over the sun exposed area that is permanent and does not respond to treatment.
	• Arsenic: Diffuse dark-brown pigmentation present in early stages on limbs and trunk (rain-drop appearance). Arsenical keratosis over palms and soles
	(c) Rare:
	HIV, Vagabond disease, PCT

Table 4.

Different clinical manifestations caused by drugs

Drugs	Specific feature
Amiodarone	• Slate grey/purple discolouration of the sun-exposed skin.
	• Photosensitive and phototoxic reaction (50% patients)
Anti-malarials	• Bluish-grey pigmentation on sun-exposed areas
	• Bluish-grey pigmentation over the hard palate
	• Diffuse pigmentation over the nail bed
	• Long-term consumption of drug (at least 4 months) required for manifestation to develop
Clofazimine	• Orange-pink to brownish-black discolouration of the skin a few weeks after consumption
	• Associated with crystal-like drug inclusion in macrophages
	• Conjunctival, corneal, internal organ
	• Reversible
Cytotoxic drugs	• Either localised or genralised
	• Include the mucous membrane, hair, and nails
	• Busuphan and doxorubicin – mucous membrane pigmentation
	• Nail pigmentation: cisplatin, doxorubicin, florouracil, bleomycin, and hydroxyurea
	• Carmustine, mechlorethamine, and fluorouracil – topical agents causing localised pigmentation
Tetracycline	Four types of minocycline-induced pigmentation
	• Type 1: most common, blue-black discolouration in areas of inflammation and scarring
	• Type 2: blue-grey pigmentation of legs Type 1 and 2 caused by minocycline-iron chelation products
	• Type 3 (also called dirty skin syndrome): muddy brown pigmentation of the sun-exposed skin resembling Addisonian pigmentation (due to minocycline-induced myelinisation)
	• Type 4: affects vermilion of lower lip, mucosa, nails Type 3/4 do not disappear with time

Vitamin B12 deficiency can lead to hyper-pigmentation of the skin that simulates Addisonian pigmentation. The skin may be the first manifestation of the condition. It is more common in darker-skinned patients. It includes skin hyper-pigmentation, vitiligo, hair changes, and recurrent angular stomatitis. Hyper-pigmentation of the extremities predominantly over the dorsum of the hands and feet, with accentuation over the terminal phalanges and inter-phalangeal joints associated with pigmentation of oral mucosa, is characteristic of vitamin B12 deficiency.[9] Pigmentation and bluish discolouration of the nails can also be seen. Vitamin B12 deficiency lowers the intra-cellular redox potential with a concomitant decrease in reduced glutathione level. Reduced glutathione has a tyrosine inhibiting effect. This leads to excess tyrosine and hence excess melanin production.[10]

Aaron et al.[11] reported glossitis in 12 out of 63 (19%) patients with vitamin B12 deficiency, which was the most common mucocutaneous manifestation, followed by skin hyper-pigmentation (19%), hair changes (9%), angular stomatitis (8%), and vitiligo (3%). Agrawala R et al.[9] reported hyper-pigmentation in a 35-year-old female with vitamin B12 deficiency masquerading Addison’s pigmentation. Megaloblastic anaemia with low-serum vitamin B12 was found, mostly due to poor dietary intake. Her hyper-pigmentation resolved with vitamin B12 supplementation. We have also noticed hyper-pigmentation over the knuckles and palmar crease in a few paediatric patients who on laboratory evaluation were found to be deficient of vitamin B12. There was also resolution of pigmentation on vitamin B12 supplementation in 14–16 weeks [Figures 4 and 5]. Pigmentation in vitamin B12 deficiency that simulates the pigmentation of Addison’s disease is a rare initial presentation, and early management can prevent various neurological complications.

Figure 4.

Diffuse pigmentation over the face (a), knuckles (b), and palmar creases (c) in a 10-year-old boy. He was found to have vitamin B12 deficiency and was started on oral methylcarbylamine

Figure 5.

An 11-year-old boy presented with the hyper-pigmentation over periungual area and knuckles (a). There was significant improvement in pigmentation after 14 weeks of starting him on oral methylcobalamine (b)

Management

Management of Addison disease requires adequate hydration and electrolyte imbalance. Lifelong supplementation of glucocorticoids and mineralocorticoids is required. With hormonal supplementation, the ACTH level decreases and hyper-pigmentation improves. Routine care includes regular doctor’s visits, special attention, and possible extra medication during the time of illness and an awareness of circumstances that may trigger an adrenal crisis, for example, dehydration/salt loss during vigorous exercise.[12] In case of Addisonian pigmentation of tubercular etiology, the patient should be started on steroid replacement therapy despite exacerbation of pulmonary tuberculosis to prevent Addisonian crisis as ATT does not improve adrenal function.[13] Steroid replacement therapy gradually improves the skin hyper-pigmentation, but the mucosal pigmentation may persist.

Conclusion

Generalized skin and mucosal hyper-pigmentation is a tell-tale sign of primary adrenal insufficiency. It precedes other manifestations by months to years. It helps in early diagnosis and prevention of adrenal crisis. The basis of Addison disease has dramatically changed from an infectious cause to auto-immune pathology. However, tuberculosis is still the predominant cause of Addison disease in developing countries like India. Addisonian pigmentation is not a disease per se; rather, it is a presentation of numerous conditions. We have provided a comprehensive approach regarding the same [Table 5]. The management of this Addisonian pigmentation mainly depends on the treatment of the underlying cause. However, an increase in clinical awareness and more studies are needed to further understand this entity regarding its numerous etiological factors and management.

Table 5.

Algorithmic approach to Addisonian pigmentation

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.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.