Background
Bullous disease of diabetes (bullosis diabeticorum) is a distinct, spontaneous, noninflammatory, blistering condition of acral skin that is unique to patients with diabetes mellitus. Bullous disease of diabetes tends to arise in long-standing diabetes or in conjunction with multiple complications. The etiology of the disease is yet unknown. In the United States, bullous disease of diabetes has been reported to occur in approximately 0.5% of patients with diabetes. Male patients have twice the risk that female patients have. [1, 2, 3, 4, 5, 6]
Kramer first reported bullous-like lesions in patients with diabetes in 1930; [7] Cantwell and Martz are credited with naming the condition bullosis diabeticorum, in 1967. [8] It is also termed bullous disease of diabetes and diabetic bullae.
While lesions typically heal spontaneously within 2-6 weeks, they often recur in the same or different locations. Secondary infections may also develop; these are characterized by cloudy blister fluid and require a culture. [9]
For patient education information, see the Diabetes Center.
Pathophysiology
The pathophysiology of bullous disease of diabetes (bullosis diabeticorum) is likely multifactorial. Patients with diabetes have been shown to have a lower threshold for suction-induced blister formation compared with nondiabetic controls, [10] and because of the acral prominence of diabetic bullae, the role of microtrauma has been speculated.
Electron microscopic evidence has also suggested an abnormality in anchoring fibrils. However, this alone does not explain the often spontaneous development of multiple lesions at several locations.
In some patients, blisters are related to ultraviolet (UV) exposure, especially in those with nephropathy. Poor blood glucose regulation (hypoglycemia [11] and hyperglycemia [12] or widely varying levels [11, 12] ) have been associated with blister formation.
Etiology
The etiology of bullous disease of diabetes (bullosis diabeticorum) is unknown. Prominent acral accentuation of bullous disease of diabetes lesions suggests a susceptibility to microtrauma-induced changes. However, most of the patients developed blisters spontaneously without history of trauma.
Many, but not all, patients with bullous disease of diabetes have nephropathy or neuropathy; some authors have hypothesized an etiologic association, possibly related to a local sub-basement membrane–zone connective-tissue alteration. Hyalinosis of small vessels noted on biopsy specimens has led some authorities to speculate microangiopathy-associated blister induction. In some, especially in patients with neuropathy, UV exposure is also thought to play a role. [11] There were reports of calcium and magnesium disturbance and abnormal carbohydrate metabolism in contribution to the disease. [13] Rarely, immunologic deposition was suspected as a cause of vasculopathy in patients with a positive direct immunofluorescence (DIF) study. [14, 15] The postulated importance of glycemic control remains to be confirmed.
Epidemiology
Bullous disease of diabetes (bullosis diabeticorum) is rare; the incidence of the disease in the population with diabetes is around 0.16% per year. [11] In the United States, the condition has been reported to occur in approximately 0.5% of patients with diabetes, although its frequency may actually be higher due to underreporting of blistering. Patients with uncomplicated or newly diagnosed disease, including type 2 diabetes, may also be affected. Rarely, bullous disease of diabetes has been reported in patients with prediabetes. [16]
The age of onset of bullous disease of diabetes typically ranges from 17-84 years, although a case in a 3-year old child has been reported. [17] Bullous disease is more frequent in adult men suffering from long-standing, uncontrolled diabetes with peripheral neuropathy, with a male-to-female ratio of 2:1. [1]
Prognosis
Bullous disease of diabetes (bullosis diabeticorum) blisters typically heal spontaneously, within 2-6 weeks. Although secondary infection may develop, the prognosis for bullous disease of diabetes is typically good. Bullous disease of diabetes lesions often heal without significant scarring, but they may be recurrent and also may lead to ulceration. [11] There have also been reports of osteomyelitis arising at a site of bullous disease of diabetes [18] and reports of amputation due to infection. [19]
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Bullous disease of diabetes (bullosis diabeticorum). Tense, noninflammatory bulla on the leg.
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Bullous disease of diabetes (bullosis diabeticorum). Unroofed blister on the leg. Note the irregular shape.
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Bullous disease of diabetes (bullosis diabeticorum). Histology of bullosis diabeticorum showing a noninflammatory blister with a subepidermal and focally intraepidermal separation (hematoxylin and eosin stain).
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Bullous disease of diabetes (bullosis diabeticorum). High-power view of the dermis beneath the blister showing capillary wall thickening (hematoxylin and eosin stain).
