Continuing Education Activity

Bullosis diabeticorum (BD), also known as diabetic bullae or bullous eruption of diabetes mellitus, is a specific type of skin lesion occurring in patients with diabetes mellitus. Kramer first reported it in 1930, and Rocca and Pereyra later described it in 1963. This activity reviews the pathophysiology and presentation of bullous diabeticorum and highlights the role of the interprofessional team in its management.

Objectives:

• Review the etiology of bullosis diabeticorum.
• Describe the histopathology of bullosis diabeticorum.
• Summarize the treatment for bullosis diabeticorum.
• Explain modalities to improve care coordination among interprofessional team members in order to improve outcomes for patients affected by bullosis diabeticorum.

Introduction

Bullosis diabeticorum (BD), also known as diabetic bullae or bullous eruption of diabetes mellitus, is a specific type of skin lesion occurring in patients with diabetes mellitus. Kramer first reported it in 1930, and Rocca and Pereyra later described it in 1963. The term “bullosis diabeticorum” was then introduced in 1967 by Cantwell & Martz.[1] In fact, the authors noticed the recurrent spontaneous blisters occurring on the extremities of patients with diabetes mellitus. Most of them had a long-standing disease with peripheral neuropathy. The lesions were asymptomatic and healed slowly without scarring in 2 to 6 weeks.[2]

Etiology

The pathophysiology of bullosis diabeticorum is not completely clear and appears to be multifactorial. In a study by Bernstein and colleagues, authors demonstrated that patients with insulin-dependent diabetes have a marked reduced threshold to suction blister development compared to age-matched normal controls, with a highly significant difference (p<0.01).[3] And because of the acral prominence of BD in patients with diabetes mellitus, the role of trauma has been speculated. However, this cannot account for the absence of BD in the vast majority of the diabetic population, with the absence in most cases of any history of trauma and the fact that these lesions resolve spontaneously.[4] As the majority of patients with diabetes mellitus with BD have associated nephropathy and neuropathy, some have suggested the role of microangiopathy in the occurring of premature aging of connective tissue and, more precisely, a local subbasement membrane zone connective-tissue alteration.[5] However, in some individuals, BD was described as the first presentation of a prediabetic state as impaired glucose tolerance.[6]

Moreover, it has been postulated in the literature the role of disturbances in calcium, magnesium, and carbohydrate metabolism.[2] Excessive exposure to ultraviolet light, especially in those with nephropathy, has also been suggested as a causative factor in a few cases. Individuals with end-stage renal failure may have mildly elevated plasma porphyrin levels, possibly contributing to the pathogenesis of blister formation.[7]

Epidemiology

The exact prevalence of BD is unknown. The majority of case stories reported in the literature were of a few small series.  In a retrospective study of 5000 patients with diabetes mellitus, conducted by Larsen and colleagues, the incidence of BD was 0.16% per year.[7] It was reported in patients from 17 to 80 years of age with a mean age of 55 years. BD more frequently presented in adult men who had long-standing uncontrolled diabetes.[8] The reported male-to-female ratio is 2:1.[9]

Histopathology

The histologic findings are heterogeneous. BD shows bullae with inconsistent levels of skin layer separation. Initial reports described intraepidermal blisters (subcorneal or suprabasal) without acantholysis, situated in most cases in the superficial part of the prickle-cell layer, whereas recent publications have usually described subepidermal bullae.[10] The combinations of subepidermal and suprabasal bullae are, however, not infrequent.[2] There have been suggestions that the level of cleavage depends on the age of the blister. Bullae are initially subepidermal, and then intraepidermal blisters repre­sent older lesions undergoing re-epithelialization.

Interestingly, the adjacent epidermis is often unremarkable. The dermis shows minimal inflammation, and microvascular changes consistent with diabetes are also present. The proteinaceous fluid contained in bullae is, most of the time, clear and sterile. However, the sub-epidermal variant can be hemorrhagic.[2]

Direct immunofluo­rescence examination is usually negative, although one report described non-specific associated immunoglobulin M and complement C3 deposits within dermal blood vessel walls.[11] Electron microscopy of fresh blisters has revealed separation in a subepidermal location, residing in the lamina lucida or below the lamina densa.[2]

History and Physical

BD characteristically starts with a sudden appearance of one or more painless, tense vesicles or bullae within normal-appearing, non-inflamed skin, generally on the acral portions of the body.[12] The most frequent locations reported in the literature are the feet, distal legs, hands, and fore­arms. Blisters particularly appear on the tips of the toes and the plantar surface of the feet.[10] They are rarely present on the trunk. The lesions are usually asymptomatic. Some patients occasionally notice a mild burning sensation. Blisters often develop ‘overnight’ and in the absence of known trauma. The vesicles and bullae range in size from few millimeters to several centimeters. Lesions typically start as tense blisters, which become flaccid and asymmetrical in shape as they enlarge. They contain a clear and sterile fluid, which may sometimes be hemorrhagic. Also, they can be filled with pus if there has been a secondary bacterial infection.

Most patients with BD have longstanding diabetes. BD has associations with both insulin-dependent and noninsulin-dependent diabetes melli­tus. Many patients have an associated polyneuropathy, retinopathy, or nephropathy. But occasionally, bullae can be a presenting sign of the disease.[10]

Evaluation

Once the diagnosis of BD is a consideration, the patient should undergo evaluation for his metabolic condition; levels of glycemia should be controlled. And if diabetes mellitus a known diagnosis, prompt screening should take place. Patients with confirmed BD should be monitored for the development of secondary infection until lesions heal entirely.[13]

Because of the higher prevalence of microangiopathic complications in patients with diabetes mellitus with BD, ophthalmological and neurological examinations are recommended. Evaluation of renal function, especially detecting microalbuminuria, should also be necessary.

Treatment / Management

No firm consensus has emerged as to the management of BD.[14] The blisters have traditionally been deemed self-limiting, with bullae said to resolve untreated within 2 to 6 weeks. Many authors have advised that the blistered skin should be left intact since it constitutes an effec­tive and sterile cover for the underlying wound. Some authors advocate a small-bore needle aspiration or placement of a small window in the blister roof and application of topical antiseptics or antibiotics to reduce discomfort and prevent secondary infections. In some cases, surgical management of BD was required with soft tissue infection, given the significant risk of osteomyelitis.[14] Recurrent BD has undergone successful treatment with autologous bone marrow mesenchymal cell transplantation therapy.[15]

Differential Diagnosis

Several disorders should merit consideration in the differential diagnosis of BD. In porphyria cutanea tarda and pseudoporphyria, the blisters are usually infracentimetric and favor the hands rather than the feet and ankles. Pseudoporphyria is not uncommon in patients with diabetes as they may develop complications including both chronic renal failure and atherosclerotic cardio­vascular disease and, thus, they may be receiving dialysis and/or diuretics. The distal extremity is also a common site for erythema multiforme and fixed drug eruptions, but the bullae usually develop on an inflammatory base. Epidermolysis bullosa acquisita and localized bullous pemphigoid, closely resembling BD, both clinically and histologically, are dif­ferentiated from BD by histologic examination and direct immunofluorescence, as well as by an accen­tuation of lesions at frictional sites in patients with epidermolysis bullosa acquisita. If there is a surrounding inflammatory skin with erythema, warmth, and tenderness, the possibility of bullous cellulitis must also be a consideration.

Prognosis

BD is more frequently a self-limiting condition and usually resolves spontaneously within a few weeks. Lesions typically heal without post-inflammatory pigmentation or residual scarring. Nevertheless, repeated and recurrent episodes are leading to ulceration, and scarring [16] have been reported.[7] Bullous symptoms can reoccur over the years.

Enhancing Healthcare Team Outcomes

Recognition of BD is essential as the differential diagnosis is extensive. The risk of consequent infection is perhaps the most pressing concern for the interprofessional team, including a primary care provider, nurse practitioner, internist, endocrinologist, and wound care nurse. The connection between BD and the degree of glycemic control in patients with diabetes mellitus remains unclear. Awareness of other potential vascular complications should always be in mind. And given that BD is generally self-limiting, treatment remains mainly supportive.