Complications and Comorbidities> Muscle, Skin and Bone>

DEFINITION

• Dermatologic manifestations of diabetes are common and come in numerous forms (Romano)
• Skin findings may help diagnosis disease (e.g. acanthosis nigricans) or reflect long-term complications of disease (e.g. necrobiosis lipoidica diabeticorum (NLD)).
• The dermatologic manifestations may be due to deposition of advanced glycosylation end-products (AGEs), infectious, autoimmune, or related to pharmacological therapy for diabetes (i.e. insulin).
• Often, skin manifestations reflect other co-existing conditions such as dyslipidemia.

EPIDEMIOLOGY

• Approximately half of all patients with diabetes will have some dermatological manifestations (Chakrabarty, Romano).
• Autoimmune skin findings are more common in T1DM than T2DM (Romano).
• Infectious skin findings are the most prevalent in poorly controlled diabetes (Romano).

DIAGNOSIS

• Diagnosis can often be made by examination of the skin.
• Occasionally, such as with NLD, punch biopsy, culture or imaging is needed to confirm diagnosis.

SIGNS AND SYMPTOMS

• Acanthosis nigricans: hyperpigmented, velvety plaques in skin folds - most commonly the axillae and flexural areas of the posterior neck. A manifestation of insulin resistance, usually in type 2 diabetes and polycystic ovarian syndrome; asymptomatic. Differential includes paraneoplastic syndrome, a sign of a gastrointestinal malignancy, or drug reaction (Higgins; Ahmed)
• Diabetic dermopathy (shin spots): groupings of macules or plaques on the lower leg, which may recede or progress; progression may involve an increase in the number of spots, enlargement of spots and the spots may become hyperpigmented and/or depressed ("shallow").  Occurs in up to 40% of patients with diabetes, men > women, usually in the setting of other microvascular complications. May be due to slowly-healing trauma.  (Ahmed; van Hatten)
• Necrobiosis lipoidica diabeticorum (NLD): begins as an violaceous patch, expanding slowly with a red border and yellow-brown central area; over time, the central area atrophies and becomes waxy with telangiectasias; ulceration occurs in 35% of cases. Rare, occuring in 0.3% of people with diabetes; typically occurs in women in 3rd to 4th decade and may appear many years before the onset of diabetes. Unless ulceration occurs, asymptomatic and only occasionally of cosmetic concern. (Ferringer; Cohen; Paron)
• Diabetic bullae:  Rapid onset of painless, tense, serous blisters on plantar surface of feet, hands and legs; usually heal in 2 to 4 weeks. Occurs in longstanding diabetes. (Romano; Ferringer; Ahmed; van Hattem; Paron)
• Yellow nails, palms or soles: common, without known pathological consequence. Unknown etiology but may be due to deposition of advanced glycosylation products or, less likely, elevated carotene. (Paron; Ahmed; Ferringer)
• Skin infections: occur in 20-60% of patients with diabetes.  1) Candida: Staphylococcus and Streptococcus especially common, affecting intertriginous areas (groin, under breasts, axillae), vagina in women, penis (balinitis) in men. Most common with poor glycemic control.  2) Necrotizing fasciitis - rapidly progressive infection of skin and soft tissue, mixed bacterial origin, consider in patients with signs of cellulitis who appear septic. 3) Malignant external otitis - invasive infection of external auditory ear canal - most commonly, pseudomonas; may spread to surrounding structures, clinical exam reveals tenderness of pinna with purulent drainage, CT or MRI needed to determine extent of bony involvement. 4) Erythrasma - common skin infection of skin folds (axillae, groin, spaces between digits, intergluteal folds), usually due to Corynebacterium.  5) Rhinocerebral mucormycosis - rare but life-threatening, occurs more often in the elderly, due to fungal infection with Zygomycetes, presents with fever, facial cellulitis, periorbital edema, facial numbness, proptosis and/or blindness, CT/MRI used to assess extent of involvement. (Romano; Ahmed; Chakrabarty, Carfrae)
• Scleroderma-like changes: Prevalence ranges from 2.5-50%; affects T1DM and T2DM, with no race or sex preference; asymmetric nonpitting induration of the skin on hands (sclerodactyly) and neck, shoulders and back (scleredema diabeticorum); often occurs with joint problems; clinical course is progressive with increasing involvement and stiffness. (Cole; Sattar; Brik; Ahmed; Ferringer; Yosipovitch)
• Reactions to insulin: 1) Lipoatrophy - areas with loss of subcutaneous fat, may be as large as 5-10 cm. May have immunological basis or due to lipolytic components of insulins. Risk increases with repeated injection at same site. Insulin absorption from effective sites can be erratic. Less common with newer insulins than with beef/pork insulin. 2) Lipohypertrophy - areas of marked subcutaneous lipid hypertrophy, often 1-15 cm circumference, raised 3-5 cm. This is the most common skin complication of insulin therapy. Also reduced with newer insulins. Like lipoatrophy, associated with injection into same site repeatedly, and can cause erratic insulin absorption. 3) Local allergic reactions - erythema, prurititis and induration. These reactions are short-lived and resolve within a few weeks. (Paron; Richardson)
• Dyslipidemias associated with diabetes: 1) Hypertriglyceridemia: if severe (>1000 mg/dl), eruptive xanthomata are showers of macular papules with white tip (triglyceride) and mildly erythematous base, most often on upper or lower extremities. Resolve with resolution of hypertriglyceridemia. 2) Hypercholesterolemia: xanthelasma (yellowish plaques in palpebrae of eye lids); tendon xanthomata; tuberous xanthomata (elbows, knees). 3) "Dysbetalipoproteinemia": palmar xanthomata, an unusual dyslipidemia associated with elevated VLDL remnants and chylomicrons; total cholesterol and triglycerides >90th percentile

CLINICAL TREATMENT

• Acanthosis nigricans (AN): treat insulin resistance with weight reduction, exercise, metformin or thiazolidinediones, although little evidence that AN responds. Lactic acid cream or retinoic acid may soften lesions; Accutane will reduce lesions but they will recur when drug stopped. (Higgins; van Hatten)
• Diabetic dermopathy (shin spots): treatment directed at the prevention of secondary infection (Chakrabarty)
• Necrobiosis lipoidica diabeticorum: no standard therapy - local steroid injections or topical creams are used with controversial results. In severe cases, skin grafting may be required.
• Diabetic bullae: usually resolves without intervention. If uncomfortable, bullae may be drained; topical antibiotics may be used to prevent secondary infection.
• Yellow skin: no treatment exists.

• Candida Infections:  keep affected area dry, treat with topical antifungals. Oral antifungals rarely required for superficial candidiasis. (Hay; Guitart)
• Cellulitis: Elevation of affected area, maintain hydration of skin to avoid cracking; empiric antibiotic therapy should cover beta-hemolytic streptococci and staphylococcus aureus and is based on local sensitivities.
• Necrotizing fasciitis: surgical evaluation and intravenous antibiotics must be delivered rapidly (Ahmed)
• Malignant external otitis: prolonged course of quinolones (6-8 weeks), debridement may be required (Ahmed; Carfrae)
• Erythrasma: erythromycin 250mg 4 times a day for 14 days (Holdiness)
• Rhinocerebral mucormycosis: urgent amphotericin B and surgical debridement

• Scleroderma-like changes: treatments have mixed results - options include photopheresis, radiotherapy, cyclosporin and high-dose penicillin; no effective treatment known for scleredema diabeticorum (Van Hattem; Ferringer)

• Lipoatrophy: rotate insulin injection site or mode of delivery. Occasionally, for severe cases, consider adding glucocorticoid to insulin for injection.
• Lipohypertrophy: rotate injection sites. Occasionally, liposuction has been used to achieve cosmetic improvement.
• Local allergic reactions: usually resolves spontaneously, but addition of glucocorticoid to insulin has been used, as has desensitization or changing to insulin pump therapy.

• Dyslipidemia: treat the underlying condition.

EXPERT COMMENTS

• Dermatologic manifestations of diabetes are common.
• Most cutaneous manifestations are autoimmune, glycemia-related, infectious or due to pharmacological therapy.
• Prognosis and treatment varies greatly depending on the type of dermatological manifestation.

REFERENCES