|
 
 |
| REVIEW ARTICLE |
|
| Year : 2021 | Volume
: 8
| Issue : 3 | Page : 133-143 |
|
Pigmentary changes associated with endocrine and metabolic disorders
Pooja Arora, Sinu Rose Mathachan
Department of Dermatology, Venereology and Leprosy, Atal Bihari Vajpayee Institute of Medical Sciences and Dr Ram Manohar Lohia Hospital, New Delhi, India
| Date of Submission | 01-Jun-2021 |
| Date of Decision | 31-Jul-2021 |
| Date of Acceptance | 24-Aug-2021 |
| Date of Web Publication | 24-Nov-2021 |
Correspondence Address:
Pooja Arora
Department of Dermatology, Venereology and Leprosy, Atal Bihari Vajpayee Institute of Medical Sciences and Dr Ram Manohar Lohia Hospital, New Delhi, Postal Code -110001
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/pigmentinternational.pigmentinternational_
Pigmentary changes in skin can act as an interface to diagnose and monitor various systemic diseases. Endocrine and metabolic disorders can directly or indirectly affect melanin synthesis pathway, thus affecting melanogenesis and skin color. Moreover, these disorders can affect the vascularity of skin and the amount of endogenous nonmelanin pigments that are responsible for skin color. Pigmentary changes can also occur in mucosa, hair, and nails and provide a clue to underlying disease. In this review, we discuss the clinical features, pathogenesis, and treatment of pigmentary changes associated with various endocrine and metabolic disorders. It is imperative for the dermatologists to be aware of these cutaneous manifestations, recognition of which can help in diagnosis and management of underlying condition.
Keywords: Cirrhosis, endocrine, hyperpigmentation, hypopigmentation, metabolic, renal
How to cite this article:
Arora P, Mathachan SR. Pigmentary changes associated with endocrine and metabolic disorders. Pigment Int 2021;8:133-43 |
| Introduction | |  |
Melanin, carotene, and oxyhemoglobin or reduced hemoglobin determine the color of normal skin. The main determinant of skin color in physiologic conditions is the melanin density. Melanin is synthesized by the melanosomes and transferred to keratinocytes. Melanogenesis is a complex process that is controlled by various factors. Systemic disorders such as endocrine and metabolic diseases can affect various steps in the melanin synthesis pathway, directly or indirectly leading to hyper- and hypopigmentation in various patterns. Under the influence of various hormones, the melanocyte-stimulating hormone (MSH) may increase or decrease leading to pigmentary changes. Apart from this, the abnormalities in the vascularity and distribution of various nonmelanin pigments such as carotene may affect skin color. This can occur in various systemic diseases such as liver and renal disorders. Dermatologists and physicians should be vigilant in identifying such dyspigmentation and correlate to any underlying systemic disease. Sometimes, these cutaneous signs can act as a presenting sign of underlying disease.
In this article, we will review the pigmentary changes associated with various endocrine and metabolic disorders. We will discuss the clinical features, pathogenesis, and treatment of such conditions.
| Methodology | | |
An electronic search was conducted in PubMed using the MESH terms and search terms such as pigmentary changes, endocrine, thyroid, diabetes, adrenal, liver cirrhosis, chronic renal failure, metabolic, nutritional, alcoholism, obesity, hemochromatosis, porphyria, hyperpigmentation, nail changes, mucosal pigmentation, graying of hair, clinical manifestations, deficiency. Articles written in English language from 1970 to December 2020 were considered for this review. [Table 1] summarizes the endocrine and metabolic disorders discussed in this review. | Table 1 Endocrine and metabolic disorders associated with pigmentary changes
Click here to view |
| Pigmentary changes in endocrine disorders | | |
Pigmentary changes in thyroid disorders
Acanthosis nigricans (AN)
It appears as symmetrical, hyperpigmented, velvety thickened skin and is characterized histopathologically by epidermal or dermal hyperplasia, hyperkeratosis, and papillomatosis with basal layer hyperpigmentation. Actual acanthosis and melanocytosis are absent in histology of AN.[1] The proliferation of epidermal keratinocytes and dermal fibroblasts in AN is induced by certain growth factors. The interaction between insulin, insulin-like growth factor 1 (IGF-1), androgens, and growth factors may explain the association between AN and obesity, endocrinopathies, or hormonal treatment.[2] In a study by Winkelmann et al., 9 out of 24 patients with benign pubertal/postpubertal AN were found to have underlying endocrinologic abnormalities.[3] AN may be associated with both hyper- and hypothyroidism. It has been found that AN is not directly related to thyroid dysfunction, but rather to the resulting effects of hypothyroidism, including obesity and subsequent insulin resistance.[4]
Carotenemia
In carotenemia, there is deposition of carotene in the subcutaneous fat and the stratum corneum causing an orange-yellow pigment with the accentuation of color in artificial light. It may be observed in patients whose conversion of carotene to vitamin A is impaired as in hypothyroidism.[5]
Diffuse hypermelanosis
Hyperpigmentation may be observed in hyperthyroidism in a distribution similar to Addison disease (creases of the palms and soles, gingiva, and buccal mucosa), and is particularly marked in darker skin types.[6]
Vitiligo
Vitiligo has been reported in association with numerous endocrine disorders [Figure 1]. In a study by Kasumagic-Halilovic et al., antithyroid autoantibodies (such as thyroglobulin antibody and thyroid peroxidase antibody) were significantly increased in vitiligo patients in comparison to healthy subjects.[7] Although the pathogenesis of vitiligo is not yet fully understood, the autoimmune hypothesis is most commonly accepted resulting from the formation of an antimelanocyte autoantibody.
Melasma
Melasma is strongly associated with female sex hormones and may occur in association with pregnancy or treatment with estrogens and/or progesterone. An association between melasma and thyroid disorders has been reported in one study but not yet confirmed [Figure 2].[8]
Skin pallor
It is the result of cutaneous vasoconstriction and increased deposition of water and mucopolysaccharides in the dermis, which alter the refraction of light.[6]
Pigmentary changes in diabetes mellitus
Acanthosis nigricans
Endocrine abnormalities, insulin resistance/type 2 diabetes mellitus (DM), polycystic ovarian syndrome (androgen and insulin excess), HAIR-AN (hyperandrogenism, insulin resistance and acanthosis nigricans) syndrome, metabolic syndrome, etc., have been found in relation to AN [Figure 3].[5] Evidence shows that AN is a useful clinical marker to identify patients susceptible to insulin resistance, and type 2 diabetes. AN occurs more frequently among children who are obese and predominantly involve the axillae, neck, inframammary folds, inguinal folds, and perineum. | Figure 3 A middle aged male with type 2 diabetes and acanthosis nigricans.
Click here to view |
Carotenemia
Impaired conversion of carotene to vitamin A is reported in diabetes. It commonly affects the palms, soles, and nasolabial folds. Lack of scleral involvement can differentiate the clinical manifestations of carotenemia from jaundice.[9]
Vitiligo
Vitiligo occurs at a greater frequency in individuals with DM. As an autoimmune condition, patients with type 1 DM appear to be at higher risk. Vitiligo has also been described in patients with type 2 diabetes. The exact pathogenesis is not clear but could be related to oxidative stress associated with diabetes.[10]
Shin spots
Diabetic dermopathy affecting up to 70% of patients with DM is observed as light brown macules and patches, commonly found on the anterior shin. Upon resolution of the lesions, patients may develop areas of atrophy or scarring.[5] This dermopathy is more prevalent in male diabetics and increases in frequency with the duration of diabetes. However, it is not related to blood glucose control. The pigmentation may be related to trauma or small-vessel disease.
Hemochromatosis
The DM develops in approximately 82% of cases of hemochromatosis. The pigmentation observed in hemochromatosis is diffused and generally characterized by a metallic gray hue, but is darker on the exposed areas, scars, extensor surfaces, and pressure points. Pigmentation is predominantly due to melanin deposition.
Pigmentary changes in disorders of adrenal glands
Cushing syndrome
(i) Diffuse hypomelanosis: Depigmentation due to suppression of MSH by high circulating levels of cortisol may be observed in Cushing syndrome.[11]
(ii) AN: It can occur secondary to weight gain and obesity associated with Cushing syndrome.
Addison disease, Nelson syndrome, and ectopic Cushing syndrome
(i) Diffuse hypermelanosis: Generalized bronze hyperpigmentation is reported in conditions such as Addison disease/primary adrenal insufficiency, ectopic Cushing syndrome [Figure 4], and adrenalectomy/Nelson syndrome.[12],[13] In the absence of a negative feedback as in Addison disease and Nelson syndrome, corticotropin-releasing hormone (CRH) levels increase, leading to increased production of adrenocorticotropic hormone (ACTH) and MSH which are generated by the cleavage of proopiomelanocortin. Both ACTH and MSH have marked promelanogenic effects. MSH and ACTH act on melanocortin receptor type 1 of melanocytes displaying melanogenic and mitogenic effects via cyclic adenosine monophosphate-dependent pathways. Receptor binding increases tyrosinase activity and melanin production, and stimulates dendrite formation.[14] The pigmentation usually is diffuse and deeper in the skin of the exposed areas, scars, areola, palmar creases, knuckles, pressure areas, extensor surfaces, and oral mucosa. In Addison disease, individuals develop hyperpigmented scars, darkening of hair, darkening of nevi, and longitudinal bands on nails. Hyperpigmentation of mucosal surfaces (tongue, the inner surface of the lip, as well as buccal and gingival mucosa) can also occur. In ectopic Cushing syndrome, there is ectopic production of ACTH/MSH in the presence of a negative feedback and decreased CRH in contrast to Addison disease and Nelson syndrome. | Figure 4 A patient with Addisonian pigmentation secondary to ectopic adrenocorticotropic hormone production due to small cell cancer of lung.
Click here to view |
(ii) Vitiligo: Vitiligo, caused by the autoimmune destruction of dermal melanocytes, occurs in 10% to 20% of individuals with autoimmune adrenalitis. Mixture of pigment loss and hyperpigmentation may be reported in patients with concurrent presence of Addison disease and vitiligo.
(iii) AN: It can occur in association with weight gain as described earlier.
Pigmentary changes in other endocrine disorders
POEMS syndrome
Cutaneous disorders are present in 68% of patients, with diffuse hyperpigmentation, and acrocyanosis being the most common pigmentary abnormalities.[15] Hyperpigmentation can be diffuse or localized, occurring mainly on the extensor surfaces, dorsum, neck, and armpits. It usually regresses in response to treatment. In a study by Miest et al., hyperpigmentation was reported in 47% of patients with POEMS syndrome and 34% of patients had acrocyanosis.[16]
Disorder of the hypothalamic-pituitary axis
(i) Acromegaly: Alterations in skin pigment may present as diffuse hyperpigmentation in approximately 40% of patients with acromegaly. Patients may develop AN due to increase in growth hormone (GH) receptor stimulation causing proliferation of dermal fibroblasts and increased IGF-1 inciting proliferation of keratinocytes.[5]
(ii) Hypopituitarism: There is an increased sensitivity to sunburn with reduced melanin content and delayed tanning probably due to decreased MSH and ACTH production in hypopituitarism.[17] Patients present with diffuse pallor particularly in the genital area, breast areolae, and face, which exhibit a decreased malar flush. Anemia and decreased cutaneous blood flow due to concurrent hypothyroidism (secondary to decreased thyroid-stimulating hormone) may further aggravate pallor.[18] Carotenemia is also reported in panhypopituitarism.
(iii) Hypogonadism: It may be associated with diffuse hypomelanosis, but the mechanism for this decrease in pigmentation is not known. There are reports suggesting testosterone/estrogen deficiency that decreases melanin pigmentation and decreases the capacity of the melanocytes to respond to solar stimulation.[19] There are reports of AN in males with different types of hypogonadism, including pituitary hypogonadism.[20],[21]
McCune–Albright syndrome
Melanotic macules (cafe au lait spots) may appear in association with precocious puberty and polyostotic fibrous dysplasia forming a clinical triad. Cafe au lait spots usually appear during the neonatal period with a “coast-of-Maine” appearance. Classically observed over the nape of the neck, base of the spine (usually respect midline), trunk, and face. Endocrinopathies including hyperthyroidism, GH excess, Cushing syndrome, and renal phosphate wasting may be associated.[22]
| Pigmentary changes in metabolic disorders | | |
Kidney disease
Chronic renal failure
Patients with chronic kidney disease stages 1 and 2 (glomerular filtration rate > 60 ml/min) usually do not have uremic or cutaneous symptoms. Cutaneous changes are usually associated with stages 3, 4, and 5 and occur in the form of xerosis, pigmentary changes, and pruritus. Pigmentary changes reported in renal disease are summarized in [Table 2]. They form the second most common cutaneous manifestation reported in patients with kidney disease and can present as pallor, yellowing of skin, hyperpigmentation, and ecchymoses.[23] The cutaneous changes can act as a presenting sign of underlying kidney disease. | Table 2 Pigmentary changes reported in patients with chronic renal failure
Click here to view |
Hyperpigmentation: The prevalence of hyperpigmentation is greater in Caucasians and Asians due to the tropical climate and greater sun exposure. In patients with chronic kidney disease, the frequency of hyperpigmentation is higher in patients with longer disease duration and severity. Hyperpigmentation occurs due to inadequate excretion of beta-MSH leading to increased levels which manifests as diffuse or localized hyperpigmentation over photo-exposed sites. Face and extremities are commonly affected. There may be hyperpigmentation of palms and soles and mucous membranes. Histopathology reveals excess melanin in basal and superficial layers of skin. Pigmentation responds to sun protection measures and use of sunscreens. Rarely, grayish-brown discoloration of skin may occur due to hemosiderosis secondary to chronic transfusions.
Nail changes: Half-and-half nails (Lindsay nails) have been described in patients with chronic renal failure which manifests as whitish discoloration of proximal one half to two-thirds of the nail with pink to brown discoloration of the distal portion. It is observed in 20% of patients with end-stage renal disease (ESRD).[24] The mechanism for this nail discoloration is unknown but may be related to increased tissue concentration of beta-MSH and edema of the nail bed. The condition may remit after renal transplant.[25]
Pigmentary changes in patients on dialysis
Pigmentary changes in patients undergoing dialysis occur due to pre-existing renal insufficiency causing changes in amount of chromogens such as melanin, hemoglobin, lipochromes, and carotenoids. A study found that the frequency of cutaneous manifestations (including pigmentary changes) was similar between dialyzed and undialyzed patients with ESRD.[26] In effect, dialysis can worsen many of these cutaneous symptoms as it is not very effective in removing many substances that are removed by a normal healthy kidney. Moreover, dialysis cannot replace the endocrine function loss in such patients which can lead to metabolic abnormalities and cutaneous complications. Deleixhe-Mauhin et al. used colorimetric measurements to assess the color of skin in patients undergoing hemodialysis and found that duration of dialysis and use of erythropoietin (EPO) did not affect the measurements.[27] Another study found that hemodiafiltration was more effective than hemodialysis in reducing skin pigmentation due to its greater ability to clear middle molecular weight substances (carotenoids, urochromes, and beta-MSH) associated with pigmentation.[28]
Liver disease
Pigmentary changes in liver cirrhosis
Jaundice: Jaundice is the most common pigmentary manifestation of liver cirrhosis.[29] Patients with hepatocellular disease have impaired canalicular excretion of bilirubin or biliary obstruction leading to hyperbilirubinemia (both conjugated and unconjugated) that manifests as jaundice. There is yellowish discoloration of skin and mucous membranes. Jaundice can be observed when serum levels of bilirubin increase above 2 mg/dl.
Hyperpigmentation: Patients with chronic liver disease may develop muddy brown hyperpigmentation over sun-exposed sites [Figure 5]. The pigmentation can be diffuse or blotchy. There is accentuation of pigmentation over the periorbital and perioral areas and over the palmar creases. Men with testicular atrophy and secondary gynecomastia may show areolar pigmentation. Metallic brown pigmentation can occur in patients with cirrhosis associated with hemochromatosis, also known as bronze diabetes. | Figure 5 A patient with alcoholic liver cirrhosis and muddy brown hyperpigmentation over face.
Click here to view |
Nail discoloration: Muehrke bands can develop in patients with chronic liver disease. Advanced disease can lead to formation of Terry’s nails in which nails appear white with a ground glass appearance with a small band of pink or brown at the tip. Terry nails can also be observed in other diseases such as chronic renal failure, DM, and congestive heart failure.[30] Azure lunulae, or bluish discoloration of lunula, can occur in patients with cirrhosis secondary to Wilson disease.
Eccrine chromhidrosis: Hyperbilirubinemia associated with liver disease can lead to eccrine chromhidrosis.[31] Direct bilirubin is water soluble and gets oxidized to green-colored biliverdin. This is secreted as green-colored sweat causing discoloration of palms and soles. This may be associated with pompholyx.
Pigmentary changes in primary biliary cirrhosis (PBC)
It is an autoimmune disorder observed in middle-aged females. Skin changes most frequently reported in PBC are xanthomatous lesions, pruritus, and melanosis. These can act as a presenting sign leading to diagnosis of the underlying liver condition.[32]
Severe pruritus results in postinflammatory hyperpigmentation and excoriations. Patient’s inability to scratch over nonaccessible areas such as the upper back can cause the butterfly sign characterized by normal skin surrounded by hyperpigmentation. According to a study, pigmentary changes can be observed in 12.4% of patients with PBC.[32] It is not clear whether pigmentation occurs due to increased melanogenesis or defective melanin degradation though there is support for the latter mechanism.[33]
Pigmentary changes due to hepatitis
Hepatitis may manifest as jaundice that can be appreciated in the skin and mucous membranes. Hepatitis C may be associated with porphyria cutanea tarda (PCT) leading to pigmentary signs associated with the latter (described below).[34] Hepatitis C virus seropositivity can be associated with autoimmune disorders such as vitiligo.
Nutritional disorders
Kwashiorkor
It is caused by deficiency of proteins with a normal caloric intake. It generally affects children 1 to 4 years of age and is the most common form of malnutrition in hospitalized children. It presents as “flaky paint” dermatitis along with lightening of hair called as “flag” sign.
Vitamin B3 (niacin) deficiency
Vitamin B3 or niacin deficiency manifests as pellagra which is characterized by a group of symptoms called as four Ds: dermatitis, diarrhea, dementia, and death, if untreated. Pellagra is caused by various factors such as inadequate diet, malabsorption, chronic alcoholism, and metabolic disorders such as Hartnup disease and Carcinoid syndrome. Cutaneous symptoms start as a photosensitive itchy rash over dorsa of hands that become edematous with appearance of vesicles and bullae that rupture to leave behind crusted erosions. Gradually the skin becomes thickened scaly and hyperpigmented. Hyperpigmentation increases and becomes the cardinal cutaneous sign.[35] Rash of pellagra is bilateral, symmetrical, and classically limited to the photo-exposed sites described as the “glove” and “gauntlet” of pellagra [Figure 6].[36] A broad hyperpigmented band may appear on the neck called as “Casal’s necklace.” Other pigmentary changes that can be observed are hyperpigmented hyperkeratotic lesions over bony prominences such as knees, ankles, and elbows. Cutaneous lesions of pellagra respond within 3 to 4 weeks to oral administration of nicotinamide or niacin (nicotinic acid) in the dose of 100 to 300 mg per day. | Figure 6 A 36-year-old male with pellagra consequent to chronic alcoholism: (a, b) hyperpigmentation over hands and feet in a “glove and gauntlet” pattern; (c) photosensitive rash over face that subsided with marked hyperpigmentation.
Click here to view |
Vitamin B12 deficiency
It manifests as Addisonian pigmentation, that is, reversible brownish black hyperpigmentation over photo-exposed sites, dorsa of hands and feet (accentuation over interphalangeal joints), knuckles [Figure 7], flexures, mucosae, palmar creases, and nails. Nails may show diffuse or longitudinal melanonychia and the pigmentation of the onychodermal band.[37] Mucosal pigmentation can be seen along with other oral findings such as angular stomatitis, Hunter glossitis, glossodynia, and recurrent ulcers. | Figure 7 A 20-year-old female presented with hyperpigmentation over the knuckles. Evaluation revealed low serum vitamin B12 levels.
Click here to view |
Diffuse hyperpigmentation is more common in dark skinned individuals. People of European descent develop spotty or reticulated pigmentation rather than generalized.[37] Recognition of hyperpigmentation is important as it may be the presenting sign of vitamin B12 deficiency. Serum B12 levels should be checked in all patients presenting with Addisonian pigmentation.[38] However, laboratory values may not correlate with actual levels. Elevated levels of methylmalonic acid is considered more sensitive and specific for diagnosis of vitamin B12 deficiency.[39]
The condition responds to vitamin B12 supplementation within 8 to 12 weeks.
Two mechanisms have been postulated for vitamin B12-induced pigmentation:- Vitamin B12 alters the intracellular redox potential causing a decrease in reduced glutathione.[40] The latter has a tyrosinase inhibiting action, hence its decrease causes stimulation of melanocytes to produce more melanin.
- Vitamin B12 deficiency causes high intracellular levels of tyrosinase, thus inducing excess melanin production.[41]
An uncommon cutaneous finding is the occurrence of reddish-brown hyperpigmentation over the lateral aspect of legs.[42]
Deficiency of vitamin B12 is associated with graying of hair which is contrary to the cutaneous pigmentation. Gray hair have a reduced tyrosinase activity causing a decrease in the number of melanin granules.[42] This could be because of altered cyanocobalamine metabolism in genetically susceptible patients.[43] Also, pernicious anemia-associated vitamin B12 deficiency may be associated with various autoimmune disorders such as vitiligo and autoimmune thyroiditis.
Folate deficiency
Unlike vitamin B12 deficiency, the relationship between folate deficiency and hyperpigmentation is poorly understood. It manifests similar to vitamin B12 deficiency as diffuse grayish-brown pigmentation of chest, back, and upper extremities. In a study conducted by Padhi et al., in 25 patients with cutaneous hyperpigmentation, the authors found isolated folate deficiency in 23.5%, vitamin B12 deficiency in 64.7%, and combined deficiency in 23.5% of patients.[44]
Vitamin C deficiency
This manifests as large areas of ecchymoses along with other skin changes such as follicular hyperkeratosis, corkscrew hair, and inflammation of gingival mucosa and bleeding.
Vitamin D deficiency
Vitamin D is responsible for skin pigmentation due to its effect on melanogenesis. Studies have shown that vitamin D increases the tyrosinase content of cultured human melanocytes by its antiapoptotic effect.[45] This may explain the association between vitamin D deficiency and vitiligo. Additionally, it has been reported that vitamin D decreases the expression of various cytokines involved in pathogenesis of vitiligo.
Vitamin K deficiency
As vitamin K is an important component of the coagulation cascade, its deficiency manifests as purpura, petechiae, and ecchymoses due to extravasation of blood into the skin.
Iron deficiency
Iron deficiency manifests as pallor. Few studies have found low serum iron levels in patients with melasma along with lower body iron stores, indicating role of iron deficiency in etiopathogenesis of this pigmentary disorder.[46] Iron supplements should be added to treatment for melasma though this needs to be further explored in larger trials.
Copper deficiency
Main features of copper deficiency are neurologic and hematologic but cutaneous changes can occur in the form of depigmented hair. Pallor can occur secondary to anemia.
Various pigmentary changes associated with nutritional disorders are summarized in [Table 3].
Pigmentary changes associated with obesity and its treatment
Obesity is linked to metabolic syndrome and peripheral insulin resistance. Pigmentary changes associated with obesity is AN which was earlier called as pseudo-AN although the term is no longer preferred.[47] AN occurs due to insulin resistance and increased insulin secretion which acts via the IGF-1 receptors to cause increased epidermal proliferation. Syndromes characterized by AN share the common feature of obesity and hyperinsulinemia [Figure 8]. Management in such cases involves lifestyle modification and weight reduction apart from various topical and procedural treatments. | Figure 8 An obese patient (body mass index: 31) with facial acanthosis nigricans.
Click here to view |
Treatment of obesity can also lead to various cutaneous changes especially after bariatric surgery as the nutritional status of patient worsens. Patients find it difficult to adhere to nutritional supplementation. Nutritional deficiencies of vitamins B12, A, C, D, and K can occur along with deficiency of other micronutrients such as iron, selenium, zinc, and copper.[48] These can cause pigmentary changes as outlines in [Table 3].
Pigmentary changes associated with alcohol abuse
Pigmentary changes in patients with alcohol abuse are related to the liver disease secondary to alcohol intake.[49] Hyperpigmentation manifests as diffuse muddy discoloration that may be localized and blotchy with accentuation of in areolar, perioral, and periorbital areas. Pigmentation along finger creases may be reported. Jaundice may manifest as yellowish discoloration of sclera. Areas of depigmentation, similar to idiopathic guttate hypomelanoses, may be observed on back, buttocks, thighs, and forearms. Chronic alcohol use may cause pigmentation similar to acquired hemochromatosis due to the underlying alcoholic cirrhosis.
Nail changes that have been described in alcoholics include Terry’s nails secondary to liver disease. Nail bed discoloration may occur due to alteration of vascular flow of nail bed. It disappears on blanching the fingertips. Multiple transverse bands that run parallel to lunula and blanch on pressure can occur prior to Terry’s nails.[50]
Pigmentary changes associated with hemochromatosis
Hemochromatosis can be primary (hereditary) or secondary (acquired). As primary hemochromatosis is an autosomal recessive condition that occurs after the age of 40 years, secondary hemochromatosis arises due to iron overload owing to blood transfusions or excessive intake. Hemochromatosis is characterized by the triad of hyperpigmentation, DM, and liver cirrhosis. Grayish-brown hyperpigmentation occurs over sun exposed areas of face, dorsa of hands, extremities, and over the inguinal area.[51] This may be associated with pigmentation of mucous membranes. Other nonpigmentary cutaneous features that have been described include pruritus, alopecia, and localized ichthyosis.
Pigmentary changes associated with porphyrias
Porphyrias are caused by deficiency of enzymes involved in heme biosynthetic pathway. There is accumulation of porphyrin precursors in the liver or bone marrow. Porphyria cutaneous tarda (PCT) is the most common porphyria and manifests as liver damage and photosensitivity. The lesions occur on dorsa of hands and forearms and on the face with formation of erosions, vesicles, and bullae that heal with hypo- or hyperpigmentation and milia. Sometimes, PCT is associated with melasma-like hyperpigmentation on face and hyperpigmentation over neck, upper chest, and hands in the preceding blisters.[52] These lesions have been found to have moderate to intense melanin density that may be related to elevated levels of circulating porphyrins. Some patients of PCT may have sclerodermoid-like plaques on sun-exposed sites observed as hypopigmented, yellow lesions surrounded by atrophy and hyperpigmentation. PCT-like changes can also reported in variegate porphyria and hereditary coproporphyria (HCP).[53]
| Conclusion | | |
Various endocrine and metabolic disorders can lead to pigmentary changes due the underlying disease or secondary mechanisms. It is important to recognize these signs as these can act as presenting sign of disease or be related to its severity. Treatment of underlying disease is important for management of these dermatologic manifestations in majority of these conditions.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| References | | |
| 1. | Demirkesen C. Skin manifestations of endocrine diseases. Turk Patoloji Derg 2015;31:145-54.  |
| 2. | Karadağ AS, You Y, Danarti R, Al-Khuzaei S, Chen W. Acanthosis nigricans and the metabolic syndrome. Clin Dermatol 2018;36:48-53. |
| 3. | Winkelmann RK, Scheen SR Jr, Underdahl LO. Acanthosis nigricans and endocrine disease. JAMA 1960;174:1145-52. |
| 4. | Kuroki R, Sadamoto Y, Imamura M et al. Acanthosis nigricans with severe obesity, insulin resistance and hypothyroidism: improvement by diet control. Dermatology 1999;198:164-6. |
| 5. | Lause M, Kamboj A, Faith EF. Dermatologic manifestations of endocrine disorders. Transl Pediatr 2017;6:300. |
| 6. | Leonhardt JM, Heymann WR. Thyroid disease and the skin. Dermatol Clin 2002;20:473-81. |
| 7. | Kasumagic-Halilovic E, Prohic A, Begovic B, Ovcina-Kurtovic N. Association between vitiligo and thyroid autoimmunity. J Thyroid Res 2011;2011:938257. |
| 8. | Muller I, Rees DA. Melasma and endocrine disorders. Pigmentary Disorders 2014;S1:001. |
| 9. | Orozco-Covarrubias L, Sáez-de-Ocariz M. Metabolic hyperpigmentation: carotenemia, pernicious anemia, acromegaly, Addison ’s disease, diabetes mellitus, and hemochromatosis. In: Durán-McKinster C, Silverberg NB, Tay Y-K, editors. Pediatric Skin of Color. New York, NY: Springer 2015 p. 117-23. |
| 10. | Raveendra L, Hemavathi RN, Rajgopal S. A study of vitiligo in type 2 diabetic patients. Indian J Dermatol 2017;62:168-70. [ PUBMED] [Full text] |
| 11. | Brooks VEH, Richards R. Depigmentation in Cushing’s syndrome. Arch Intern Med 1966;117:677-80. |
| 12. | Koppers LE, Palumbo PJ. Pigmentation and the endocrinologist. Med Clin North Am 1972;56:1041-9. |
| 13. | Patel J, Eloy JA, Liu JK. Nelson’s syndrome: a review of the clinical manifestations, pathophysiology, and treatment strategies. Neurosurg Focus 2015;38:E14. |
| 14. | Benner BJ, Alsma J, Feelders RA. Hyponatraemia and hyperpigmentation in primary adrenal insufficiency. BMJ Case Rep 2019;12:e227200. |
| 15. | Marinho FS, Pirmez R, Nogueira R, Cuzzi T, Sodré CT, Silva M. Cutaneous manifestations in POEMS syndrome: case report and review. Case Rep Dermatol 2015;7:61-9. |
| 16. | Miest RY, Comfere NI, Dispenzieri A, Lohse CM, el‐Azhary RA. Cutaneous manifestations in patients with POEMS syndrome. Int J Dermatol 2013;52:1349-56. |
| 17. | Ortonne JP, Mosher DB, Fitzpatrick TB. Hypomelanosis associated with endocrine disorders. In: Ortonne J-P, Mosher DB, Fitzpatrick TB, editors. Vitiligo and Other Hypomelanoses of Hair and Skin. Boston, MA: Springer 1983 p. 473-4. |
| 18. | Geller JL, Braunstein GD. Dermatologic manifestations of hypopituitarism. Clin Dermatol 2006;24:266-75. |
| 19. | Hamilton JB, Hubert G. Photographic nature of tanning of the human skin as shown by studies of male hormone therapy (letter). Science 1938;88:481. |
| 20. | Matsuoka LY, Wortsman J, Gavin JR, Goldman J. Spectrum of endocrine abnormalities associated with acanthosis nigricans. Am J Med 1987;83:719-25. |
| 21. | Sheldon SA, Curtis AC. Juvenile acanthosis nigricans associated with pituitary hypogonadism. Arch Dermatol 1955;72:63-7. |
| 22. | Dumitrescu CE, Collins MT. McCune-Albright syndrome. Orphanet J Rare Dis 2008;3:1-2. |
| 23. | Blaha T, Nigwekar S, Combs S, Kaw U, Krishnappa V, Raina R. Dermatologic manifestations in end stage renal disease. Hemodial Int 2019;23:3-18. |
| 24. | Galperin TA, Cronin AJ, Leslie KS. Cutaneous manifestations of ESRD. Clin J Am Soc Nephrol 2014;9:201-18. |
| 25. | Brewster UC. Dermatologic manifestations of end-stage renal disease. Hospital Physician 2006;42:31-5. |
| 26. | Khanna D, Singal A, Kalra OP. Comparison of cutaneous manifestations in chronic kidney disease with or without dialysis. Postgrad Med J 2010;86:641-7. |
| 27. | Deleixhe-Mauhin F, Krezinski JM, Rorive G, Piérard GE. Quantification of skin color in patients undergoing maintenance hemodialysis. J Am Acad Dermatol 1992;27:950-3. |
| 28. | Moon SJ, Kim DK, Chang JH et al. The impact of dialysis modality on skin hyperpigmentation in haemodialysis patients. Nephrol Dial Transplant 2009;24:2803-9. |
| 29. | Dogra S, Jindal R. Cutaneous manifestations of common liver diseases. J Clin Exp Hepatol 2011;1:177-84. |
| 30. | Jemec GB, Kollerup G, Jensen LB, Mogensen S. Nail abnormalities in nondermatologic patients: prevalence and possible role as diagnostic aids. J Am Acad Dermatol 1995;32:977-81. |
| 31. | Jaiswal AK, Ravikiran SP, Roy PK. Red eccrine chromhidrosis with review of literature. Indian J Dermatol 2017;62:675. [ PUBMED] [Full text] |
| 32. | Koulentaki M, Ioannidou D, Stefanidou M et al. Dermatological manifestations in primary biliary cirrhosis patients: a case control study. Am J Gastroenterol 2006;101:541-6. |
| 33. | Mills PR, Skerrow CJ, MacKie RM. Melanin pigmentation of the skin in primary biliary cirrhosis. J Cutan Pathol 1981;8:404-10. |
| 34. | Chuang TY, Brashear R, Lewis C. Porphyria cutanea tarda and hepatitis C virus: a case-control study and meta-analysis of the literature. J Am Acad Dermatol 1999;41:31-6. |
| 35. | Karthikeyan K, Thappa DM. Pellagra and skin. Int J Dermatol 2002;41:476-81. |
| 36. | Wan P, Moat S, Anstey A. Pellagra: a review with emphasis on photosensitivity. Br J Dermatol 2011;164:1188-200. |
| 37. | Carmel R. Hair and fingernail changes in acquired and congenital pernicious anemia. Arch Intern Med 1985;145 484-5. |
| 38. | Jithendriya M, Kumaran S, Ishwara BP. Addisonian pigmentation and vitamin B 12 deficiency: a case series and review of the literature. Cutis 2013;92:94-9. |
| 39. | Langan RC, Goodbred AJ. Vitamin B12 deficiency: recognition and management. Am Fam Physician 2017;96:384-9. |
| 40. | Lin SH, Sourial NA, Lu KC, Hsueh EJ. Imerslund-Grasbeck syndrome in a Chinese family with distinct skin lesions refractory to vitamin B12. J Clin Pathol 1994;47:956-8. |
| 41. | Lee SH, Lee WS, Whang KC, Lee SJ, Chung JB. Hyperpigmentation in megaloblastic anemia. Int J Dermatol 1988;27:571-5. |
| 42. | Aroni K, Anagnostopoulou K, Tsagroni E et al. Skin hyperpigmentation and increased angiogenesis secondary to vitamin B12 deficiency in a young vegetarian woman. Acta Derm Venereol 2008;88:191-2. |
| 43. | Niiyama S, Mukai H. Reversible cutaneous hyperpigmentation and nails with white hair due to vitamin B12 deficiency. Eur J Dermatol 2007;17:551-2. |
| 44. | Padhi S, Sarangi R, Ramdas A et al. Cutaneous hyperpigmentation in megaloblastic anemia: a 5 year retrospective review. Mediterr J Hematol Infect Dis 2016;8:e2016021. |
| 45. | AlGhamdi K, Kumar A, Moussa N. The role of vitamin D in melanogenesis with an emphasis on vitiligo. Indian J Dermatol Venereol Leprol 2013;79:750-8. [ PUBMED] [Full text] |
| 46. | Qazi I, Dogra NK, Dogra D. Serum iron profile in female patients of melasma: a case control study. Asian Pac J Health Sci 2017;4:141-6. |
| 47. | Hirt PA, Castillo DE, Yosipovitch G, Keri JE. Skin changes in the obese patient. J Am Acad Dermatol 2019;81:1037-57. |
| 48. | Rosen J, Darwin E, Tuchayi SM, Garibyan L, Yosipovitch G. Skin changes and manifestations associated with the treatment of obesity. J Am Acad Dermatol 2019;81:1059-69. |
| 49. | Smith KE, Fenske NA. Cutaneous manifestations of alcohol abuse. J Am Acad Dermatol 2000;43:1-16. |
| 50. | Jensen O. White fingernails preceded by multiple transverse white bands. Acta Derm Venereol (Stockh) 1981;61:261-2. |
| 51. | Chevrant-Breton J, Simon M, Bourel M, Ferrand B. Cutaneous manifestations of idiopathic hemochromatosis. Study of 100 cases. Arch Dermatol 1977;113:161-5. |
| 52. | Held JL, Silvers DN, Grossman ME. Hyperpigmentation of the lower extremities. Associated with porphyria cutanea tarda. Arch Dermatol 1989;125:297-9. |
| 53. | Bleasel NR, Varigos GA. Porphyria cutanea tarda. Australas J Dermatol 2000;41:197-206. |
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]
[Table 1], [Table 2], [Table 3]
|
Search Pubmed for