Cutaneous Manifestations of Endocrinologic Disease

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How does endocrinologic disease cause skin disorders?

Endocrinologic disease can produce cutaneous changes in several different ways:

• Hormones interact with cell surface receptors to regulate cellular function, and many cell types in skin have such hormone receptors. This means that hormone levels can directly alter skin metabolism. For example, both skin and skin appendages express thyroid hormone receptors, and thyroid hormones can alter expression of keratins by keratinocytes.

• Hormone excess or deficiency may affect the skin indirectly, rather than through specific hormone/hormone receptor interactions. For example, the hyperglycemia of diabetes results in impaired immune function and a predisposition to infection.

• Other unusual skin disorders, such as necrobiosis lipoidica diabeticorum, are highly associated with endocrine disease, but the pathogenesis is poorly understood.

Antonini D, Sibilio A, Dentice M, Missero C. An intimate relationship between thyroid hormone and skin: regulation of gene expression. Front Endocrinol . 2013;4:104.

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What is necrobiosis lipoidica?

Necrobiosis lipoidica is a granulomatous inflammatory skin condition that nearly always involves the pretibial surface. It is highly associated with diabetes, but certainly all diabetics do not get necrobiosis lipodica. Early lesions present as nondiagnostic erythematous papules or plaques that evolve yellow-brown plaques, with overlying skin atrophy and dilated blood vessels ( Fig. 35.1 A ). Fully developed pretibial lesions are essentially diagnostic, simply because of the clinical appearance and anatomic site. Later lesions may ulcerate ( Fig. 35.1 B).

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Do all patients with necrobiosis lipoidica have diabetes and how many diabetics develop the condition?

In a study of 171 patients with necrobiosis lipoidica, about 60% had diabetes. Moreover, many patients subsequently developed diabetes, had abnormal glucose tolerance tests, or had a strong family history of diabetes. Only about 10% of patients were not in a high-risk group to develop diabetes. In a more recent study with 65 patients, 22% either had or developed diabetes. Patients with necrobiosis lipoidica should be screened for diabetes. However, only about 0.3% of patients with diabetes develop necrobiosis lipoidica. The condition is most often seen in adults with type II diabetes, but it can occur in juvenile diabetes, as well. To solidify this knowledge, the following phrase if often employed: “Most cases of necrobiosis lipoidica are associated with diabetes, but no many diabetics develop necrobiosis lipoidca.”

Grillo E, Rodriguez-Muñoz D, González-Garcia A, et al. Necrobiosis lipoidica. Aust Fam Physician . 2014;43:129–130.

Hammer E, Lilienthal E, Hofer SE, et al. Risk factors for necrobiosis lipoidica in Type 1 diabetes mellitus. Diabet Med . 2017;34:86–92.

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Does glucose control affect necrobiosis lipoidica diabeticorum?

It is unclear whether tighter glycemic control (i.e., better control of diabetes) impacts the clinical course of necrobiosis lipoidica. In adults, Cohen et al. concluded that better glucose control might prevent presentation of the lesions. In children, diabetics with necrobiosis lipoidica had higher levels of hemoglobin A1c. There are several reports of resolution of necrobiosis lipoidica with pancreas transplant. At this juncture, the answer is not known with certitude.

Cohen O, Yaniv R, Karasik A, et al. Necrobiosis lipoidica and diabetic control revisited. Med Hypotheses. 1996;46(4):348–350.

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What other skin findings are associated with insulin resistance?

Acanthosis nigricans is highly associated with insulin resistance, and it presents as velvety, hyperpigmented plaques, most often in intertriginous areas, such as the neck folds and axillae ( Fig. 35.2 ). It is often described by patients as “dirty skin” that is “impossible to clean.”

Insulin-like growth factors produced by the liver, in response to high levels of circulating insulin, are thought to bind epidermal growth factor receptors, or other receptors in the skin, leading to the changes of acanthosis nigricans. The condition is found in 30%–50% of patients with diabetes, and it correlates with obesity and insulin resistance. Acanthosis nigricans may predict the development of diabetes in persons at higher risk.

Videira-Silva A, Albuquerque C, Fonseca H, et al. Acanthosis nigricans as a clinical marker of insulin resistance among overweight adolescents. Ann Pediatr Endocrinol Metab . 2019;24:99–103.

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Is diabetes the only condition associated with acanthosis nigricans?

No. Other endocrine diseases, such as Cushing’s syndrome (with excess cortisol), acromegaly (with excess growth hormone), polycystic ovarian disease, or medications that promote hyperinsulinemia, may be associated with acanthosis nigricans. So-called “malignant” acanthosis nigricans can be a paraneoplastic condition associated with certain malignancies, most commonly gastrointestinal adenocarcinomas. In fact, oral involvement of acanthosis nigricans always suggests a paraneoplastic cause.

Higgins S, Freemark M, Prose N. Acanthosis nigricans: a practical approach to evaluation and management. Dermaitol Online J. 2008;14(9):2.

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What bacterial infections are more common in diabetic patients?

Cutaneous bacterial infections are more common and may be more severe in diabetics. Diabetic foot ulcers are a leading cause of morbidity and health care cost. Diabetic neuropathy (numbness) prevents recognition of injury, and hyperglycemia impairs white blood cell function, allowing bacterial infection. Staphylococcal folliculitis or skin abscesses are common in diabetics, but often respond well to antibiotics and surgical drainage. Diabetic patients may develop necrotizing infections of the external ear caused by Pseudomonas aeruginosa . There is evidence that diabetes is a risk factor for latent tuberculosis infection.

Lee MR, Huang YP, Kuo YT, et al. Diabetes mellitus and latent tuberculosis infection: a systematic review and metaanalysis. Clin Infect Dis . 2017;64:719–727.

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What superficial fungal skin infections are common in diabetic patients?

Candidiasis, usually caused by Candida albicans , is more common in diabetics. Mucocutaneous candidiasis is characterized by white adherent exudate on erythematous skin, often with satellite pustules. Candidal vulvovaginitis is extremely common. Perianal dermatitis in men or women may be caused by Candida . Other forms of candidiasis include thrush (infection of oral mucosa), perlèche (angular cheilitis), intertrigo (infection of skin folds), erosio interdigitalis blastomycetica chronica (finger webspace infection), paronychia (infection of the soft tissue around the nail plate), and onychomycosis (infection of the nail). The mechanism appears to involve increased levels of glucose that serve as a substrate for Candida species to proliferate. Patients with recurrent cutaneous candidiasis of any form should be screened for diabetes.

Dermatophytosis is also common in diabetics, but also in the general population. A recent epidemiologic study found that among all dermatophyte infections, Trichophyton rubrum was the most often isolated. Tinea pedis (“athlete’s foot”) was most common, followed by tinea unguium (nail infection), tinea corporis (“ringworm”), tinea cruris (“jock itch”), tinea manuum (hand involvement), and tinea capitis (scalp infection), including kerion.

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Are there more dangerous deep fungal infections associated with diabetes?

Rarely, mucormycosis will complicate diabetic ketoacidosis, and it represents a severe and progressive soft tissue infection caused by saprophytic fungi of the Mucor , Rhizopus , and Absidia families. These types of infection are poorly responsive to systemic antifungals and may be quickly and abruptly fatal.

Petrikkos G, Tsioutis C. Recent advances in the pathogenesis of mucormycoses. Clin Ther. 2018;40:894–902.

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Why are diabetic patients in ketoacidosis particularly susceptible to mucormycosis?

The fungi involved in mucormycosis present in diabetic ketoacidosis because the organisms prefer a lower pH, grow rapidly with higher glucose levels, and can utilize ketones as an energy substrate.

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