In part 1 last month, we looked at three of seven dermatologic conditions associated with diabetes. Now, we’ll review the four others, considering factors involved in their pathogenesis and current management strategies.

Acanthosis nigricans

Acanthosis nigricans (AN) is characterized by hyperpigmentation and velvet-textured plaques with a symmetrical distribution, especially in the skin folds.

Classification:

• Type I: AN associated with malignancy
  • adenocarcinoma of the GI tract (60% gastric), lung and breast
• Type II: Familial AN
• Type III: AN associated with obesity, insulin-resistant states, and endocrinopathy
  • diabetes mellitus, acromegaly, polycystic ovarian syndrome, Cushing’s syndrome, hypothyroidism, Addison’s disease, hyperandrogenic states
  • Prader-Willi syndrome, Down’s syndrome, Wilson’s disease
  • drugs
    - oral contraceptives
    - glucocorticoids
    - testosterone

Up to 40% of patients with type II diabetes may have AN. It’s thought to be caused by factors that stimulate epidermal keratinocyte and dermal fibroblast proliferation. In benign forms of AN, the factor may be insulin or an insulin-like growth factor. In AN associated with malignancy, a substance secreted either by the tumour or in response to the tumour may be responsible. Exogenous medications have also been implicated as etiologic factors.

Clinical findings

• hyperpigmentation due to hyperkeratosis and clinical thickening rather than to melanin accumulation
• tripe palms (acanthosis palmaris) refers to thickened velvety palms that are associated with cancer in 95% of cases!

Differential diagnosis

• intertriginous granular parakeratosis
• confluent and reticulated papillomatosis (Gougerot-Carteaud syndrome)
• Dowling-Degos’ disease

Investigations

• usually a clinical diagnosis
• a biopsy if diagnosis is in doubt
• screening for associated conditions

Treatment

• Treat the underlying condition
  • weight loss (if occurring with obesity)
  • underlying endocrinopathy
  • find and remove causal tumour
• Specific treatments
  • topical retinoids (e.g. topical tretinoin)
  • topical calcipotriol
  • keratolytics (e.g. urea, salicylic acid)
  • insulin sensitizers (e.g. metformin, rosiglitazone)
  • systemic retinoids (e.g. acitretin)
  • laser

Granuloma annulare

Granuloma annulare (GA) is a common, chronic and self-resolving dermatosis characterized by annular papules and plaques without any scale. Women are affected twice as often as men. All age groups and races are susceptible with the highest incidence found in children and young adults.

There are five types:

• localized
• generalized (disseminated)
• perforating
• subcutaneous
• patch-type

Of these, generalized GA may be associated with DM. The association is weak, and reported mainly through case reports. If a patient has generalized GA, there’s a 20% chance of having diabetes, compared to only 10% in those with localized GA.

The pathogenesis is largely unknown. One possible trigger is UV exposure. GA has a predilection for sun-exposed areas and exacerbations are sometimes noted in the summer months. Other triggers are thought to include areas previously affected by zoster, HIV, EBV, TB, the Koebner phenomenon (trauma-induced), and insect bites. GA may represent a delayed-type hypersensitivity reaction to an unknown antigen in the dermis and subcutaneous tissue. In rare cases, fascia and tendons are affected causing sclerosis.

Clinical findings

Lesions are typically smooth and skin-coloured, violaceous or pink firm nodules that coalesce to form a beaded ring. Sometimes lesions are pruritic.

Distribution

• symmetrical
• upper trunk, proximal upper extremities, including the nape of the neck with face, and genital sparing
• hundreds to thousands of lesions < 5 cm in diameter

Diagnosis

• skin biopsy
• investigate for presence of diabetes

Course

• duration is typically 4 years, but can be less than a year or more than 10

Treatment

• Generalized cases present a major treatment challenge
• Approach is systemic rather than topical
  • as with topical agents, systemic agents may not prevent recurrence upon discontinuation
• no sound evidence for one agent over another
• systemic steroids at high doses are effective but not curative, with rapid recurrence following discontinuation
• Medications
  • isotretinoin
  • tetracycline 500 mg bid with nicotinamide 500 mg tid
  • phototherapy (i.e. PUVA)
  • antimalarials
  • pentoxifylline 400 mg tid
  • dapsone 100 mg od to bid
• For severe cases:
  • cyclosporine
• infliximab

Eruptive xanthomas

Eruptive xanthomas refers to an eruption of yellowish-red papules associated with underlying hypertriglyceridemia. It can be primary or secondary.

• Primary
  • endogenous familial hypertriglyceridemia
  • familial deficiency of apoprotein CII
  • lipoprotein lipase deficiency
• Secondary
  • alcohol abuse
  • chronic renal failure
  • diabetes mellitus
  • drugs (estrogens, corticosteroids, systemic retinoids)
  • high caloric intake
  • hypothyroidism
  • obesity

Clinical findings

• small, yellowish-orange to reddish-brown papules 1-4 mm in diameter
• appear in crops over entire body
• erythematous halo, due to triglyceride component that may produce tenderness and pruritus
• koebnerization

Treatment

• identification and treatment of primary and secondary causes of the hypertriglyceridemia
• dietary and pharmacologic lowering of the circulating triglycerides to reasonable levels will result in quick resolution of eruptive lesions
  • failure to treat high triglycerides could lead to acute pancreatitis or atherosclerosis

Scleredema

Three clinical subtypes of scleredema:

• post-febrile illness (often streptococcal), most common, rapid onset, but resolves within a few months
• monoclonal gammopathy of unknown significance (MGUS) or multiple myeloma, gradual onset
• scleredema diabeticorum

Scleredema diabeticorum

Scleredema diabeticorum is characterized by stiffening and hardening of the subcutaneous tissues, as if infiltrated with paraffin wax. It occurs 10 times more often in men than in women. Risk factors include obesity and insulin-dependent diabetes. There are often both micro- and macrovascular underlying complications from diabetes.

Clinical findings

• insidious onset
• induration and erythema of posterior neck and back
• sharp step-off from involved to normal skin
• no visceral involvement

Pathogenesis

Unknown, but possible theories include the following:

• autoimmune, sensitization to collagen by products of an infectious agent
• affected collagen is glycosylated and resistant to breakdown by collagenase
• microvascular damage and hypoxia stimulate collagen and mucin synthesis

Diagnosis

Biopsy shows findings identical to other types of scleredema

Treatment

• hyperglycemic control doesn’t affect the course of the disease
• mainly anecdotal evidence:
  • psoralen plus UVA (PUVA)
  • oral or topical corticosteroids
  • aggressive therapy for disabling cases/systemic involvement
  • pulse dose cyclosporine
  • low-dose methotrexate
  • thalidomide
  • electron beam therapy
  • chemotherapy may improve skin texture in cases associated with multiple myeloma