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 diabetic patients. Male patients have twice the risk as female patients.[1, 2, 3, 4, 5]
Kramer first reported bullous-like lesions in diabetic patients in 1930[6] ; Rocca and Pereyra first characterized this as a phlyctenar (appearing like a burn-induced blister) in 1963.[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]
The clinician should consider direct immunofluorescence (DIF) studies to exclude histologically similar entities (eg, noninflammatory bullous pemphigoid, epidermolysis bullosa acquisita, porphyria cutanea tarda, other bullous porphyrias), as DIF studies are only rarely positive in bullosis diabeticorum.[10, 11]
Pseudoporphyria blistering due to photosensitizing drugs, chronic dialysis regimens, or ultraviolet A tanning devices should also be considered.
Specific treatment is unwarranted unless secondary infections (eg, staphylococcal) occur, thereby warranting antibiotic therapy. However, aspiration of fluid from lesions using a small-bore needle might help prevent accidental rupture.
See Type 1 Diabetes Mellitus and Type 2 Diabetes Mellitus for complete information on these topics.
For patient education information, see the Diabetes Center.
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,[12] 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 UV exposure, especially in those with nephropathy. Poor blood glucose regulation (hypoglycemia[13] and hyperglycemia[14] , or widely varying levels[13, 14] ) has been associated with blister formation.
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 blister 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.[13] There were reports of calcium and magnesium disturbance and abnormal carbohydrate metabolism in contribution to the disease.[15] Rarely, immunological deposition was suspicion as a cause of vasculopathy in patients with positive DIF.[11, 16] The postulated importance of glycemic control remains to be confirmed.
Bullous disease of diabetes (bullosis diabeticorum) is rare, with only about 100 cases reported. Incidence of the disease is around 0.16% per year.[13] In the United States, bullous disease of diabetes has been reported to occur in approximately 0.5% of diabetic patients, 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, the disease has been reported in a prediabetes patient.[17]
The age of onset of bullous disease of diabetes typically ranges from 17 to 84 years, although a case in a 3-year old child has been reported.[18] 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]
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.[13] There have also been reports of osteomyelitis arising at a site of bullous disease of diabetes[19] and reports of amputation due to infection.[20]
Bullous disease of diabetes (bullosis diabeticorum) blisters occur spontaneously and abruptly, often overnight, and usually without known antecedent trauma. Most frequently, it is observed as a unilateral lesion involving the foot or leg, although bilateral lesions as well as multiple lesions have been reported; other regions such as the trunk, arms, and hands can be affected.[2] The tense blisters are usually large and asymmetrical in shape and filled with clear fluids, but hemorrhagic blisters have been reported.[21] Blisters tend to be asymptomatic, although mild discomfort or burning has been described at onset.[2] Bullous disease of diabetes blisters heal spontaneously within 2-6 weeks of onset.[1] During the healing process, the fluid leaks, leaving a darkened crust over the affected area that dissolves over time.[2]
The goals of the physical examination should include determining the location and physical characteristics of lesions, developing a useful differential diagnosis, and determining the need for biopsy to secure a correct diagnosis and for culture to identify secondary infections that may require treatment.
Common findings of bullous disease of diabetes (bullosis diabeticorum) include tense, nontender blisters arising on nonerythematous skin (see the image below).
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Bullous disease of diabetes (bullosis diabeticorum). Tense noninflammatory bulla on the leg.
Blisters tend to be large (from 0.5-17 cm in diameter), often with an irregular shape, simulating a burn. Some blisters may also be flaccid. Although blisters typically occur on the feet or lower legs, they also may occur on fingers, toes, hands, and arms. (See the image below.)
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Bullous disease of diabetes (bullosis diabeticorum). Unroofed blister on the leg. Note the irregular shape.
Rarely, nonacral sites (eg, trunk) may be involved.
The clinical workup of bullous disease of diabetes (bullosis diabeticorum) is fairly straightforward. Approaches range from culture to skin biopsy in order to more clearly differentiate the condition from other clinically similar conditions and identify secondary infections that might require treatment.
Cultures are only warranted if secondary bacterial infections are suspected. If bullous disease of diabetes blister fluid is cloudy instead of clear, the clinician should consider excluding secondary bacterial infection with culture of the blister fluid.
Should a patient present with prominent involvement of the dorsal hands, evaluation of porphyrin levels is warranted. Levels are normal in persons with bullous disease of diabetes. Elevated levels indicate porphyria cutanea tarda or another blistering porphyria. Individuals with end-stage renal disease may have mildly elevated plasma porphyrin levels, possibly contributing to the total pathogenesis of blister formation.
No primary immunologic abnormality is noted in bullous disease of diabetes. Although nonspecific capillary-associated immunoglobulin M and C3 and IgG deposition in superficial capillary basement membrane have been reported, albeit rarely,[11, 16] immunofluorescence findings have not been consistently reproduced by others, and direct immunofluorescence findings are usually negative.[22] However, immunofluorescence studies may be required to exclude clinically similar conditions (eg, bullous pemphigoid, epidermolysis bullosa acquisita, porphyrias) that typically show deposition of C3 and IgG along the basement membrane zone.
Shave biopsy or excisional/incisional biopsy can help distinguish bullous disease of diabetes from clinically similar conditions. For routine histologic sections, the clinician should include the blister and portions of the underlying dermis in the biopsy specimen and submit it in formalin.
Histologic features of bullous disease of diabetes are not entirely specific; lesions have a heterogeneous histologic presentation. Many of the reported cases describe a separation in the superficial epidermis within the superficial part of the spinous layer.
The blister plane may also appear in a subcorneal, intraepidermal, or subepidermal location; electron microscopy of fresh blisters has revealed separation in a subepidermal location, residing in the lamina lucida or the sublamina densa.[15] Anchoring fibrils and hemidesmosomes are reported absent or decreased in early blisters (see the image below).
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Bullous disease of diabetes (bullosis diabeticorum). Histology of bullosis diabeticorum showing a noninflammatory blister with a subepidermal and foca....
Note that the variable blister plane may be related to the blister age, because reepithelialization can occur within days of blister onset. The blister cavity contains sterile proteinaceous fluid; an inflammatory component is absent or insignificant.
Surrounding epidermis does not show significant change; however, rare reports describe associated spongiosis and degenerative keratinocytic pallor. Acantholysis is absent. Dermal changes (eg, capillary wall thickening, dermal sclerosis) may reflect the patient's underlying diabetes mellitus (see the image below). Caterpillar bodies typical of porphyria have been reported in lesions of bullous disease of diabetes.
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Bullous disease of diabetes (bullosis diabeticorum). High-power view of the dermis beneath the blister showing capillary wall thickening (hematoxylin ....
Specific treatment of bullous disease of diabetes (bullosis diabeticorum) is unnecessary because the condition is self-limiting. The blister should be left intact whenever possible to serve as a sterile dressing and to avoid secondary infection. Drug therapy (ie, antibiotics) is only warranted when secondary staphylococcal infection is present. For recurrent lower limb bullous diabeticorum, successful treatment with autologous bone marrow mesenchymal cell transplantation therapy has been reported.[23]
See Diabetic Ulcers, Type 1 Diabetes Mellitus, and Type 2 Diabetes Mellitus for more information.
Aspiration of fluid from bullous disease of diabetes lesions with sterile technique using a small-bore needle may prevent accidental rupture. Immobilization may prevent damage to the blister. Secondary tissue necrosis may necessitate debridement and possible tissue grafting. Aggressive wound healing intervention, as enacted with diabetic ulcers, is critical, should the blister become unroofed. Patients with confirmed bullous disease of diabetes should be monitored for development of secondary infection until lesions heal entirely.
See Diabetic Foot Infections for more information on this topic.
The American Diabetes Association guidelines for management of diabetes include these general recommendations for foot care[24] :
Feet inspected at every visit for patients with evidence of sensory loss or prior ulceration or amputation and comprehensive foot evaluation for others at least annually to identify risk factors for ulcers and amputations.
Foot examination should include inspection of the skin, assessment of foot deformities, neurologic assessment, and vascular assessment including pulses in the legs and feet.
Patients with symptoms of claudication or decreased or absent pulses should be referred for ankle-brachial index and for further vascular assessment as appropriate.
A multidisciplinary approach is required for management of foot ulcers and high-risk feet (eg, dialysis patients and those with Charcot foot, prior ulcers, or amputation).
For diabetic patients with smoking history or who have prior history of lower extremity complications, loss of protective sensations, structural abnormalities or peripheral artery disease should be referred to foot care specialist for ongoing preventive care and lifelong surveillance.
General preventive foot selfcare education should be given to all patients with diabetes.
The use of specialized footwear is recommended for high-risk patients with diabetes including those with severe neuropathy, foot deformities or history of amputation.
Wounds without evidence of soft-tissue or bone infection do not require antibiotic therapy.
Empiric antibiotic therapy can be narrowly targeted at gram-positive cocci in acute infections.
Chronic, previously treated, or severe infections require broad-spectrum regimens and should be referred to specialized care centers.
What is bullous disease of diabetes (bullosis diabeticorum)?What is the pathophysiology of bullous disease of diabetes (bullosis diabeticorum)?What causes bullous disease of diabetes (bullosis diabeticorum)?What is the prevalence of bullous disease of diabetes (bullosis diabeticorum)?What is the prognosis of bullous disease of diabetes (bullosis diabeticorum)?Which clinical history findings are characteristic of bullous disease of diabetes (bullosis diabeticorum)?Which physical findings are characteristic of bullous disease of diabetes (bullosis diabeticorum)?Which conditions are included in the differential diagnoses of bullous disease of diabetes (bullosis diabeticorum)?What are the differential diagnoses for Bullous Disease of Diabetes (Bullosis Diabeticorum)?How is bullous disease of diabetes (bullosis diabeticorum) diagnosed?What is the role of immunofluorescence in the workup of bullous disease of diabetes (bullosis diabeticorum)?What is the role of skin biopsy in the workup of bullous disease of diabetes (bullosis diabeticorum)?How is bullous disease of diabetes (bullosis diabeticorum) treated?What is the role of aspiration and debridement in the treatment of bullous disease of diabetes (bullosis diabeticorum)?What are the ADA guidelines on diabetic foot care?
Sofia Junaid Syed, MD, MPH, Medical Director of Diabetes Network, Director of Thyroid Clinic, Assistant Division Chief of Endocrinology, Bassett Healthcare Network; Adjunct Assistant Clinical Professor of Medicine, Columbia University College of Physicians and Surgeons
Disclosure: Nothing to disclose.
Coauthor(s)
Panadeekarn (Natty) Panjawatanan, MD, Resident Physician, Department of Internal Medicine, Bassett Medical Center
Disclosure: Nothing to disclose.
Vijaykumar Sekar, MD, MBBS, Resident Physician, Department of Internal Medicine, Bassett Medical Center
Disclosure: Nothing to disclose.
Chief Editor
Dirk M Elston, MD, Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine
Disclosure: Nothing to disclose.
Additional Contributors
Jacqueline M Junkins-Hopkins, MD, Associate Professor, Director, Division of Dermatopathology and Oral Pathology, Department of Dermatology, Johns Hopkins Medical Institutions
Disclosure: Nothing to disclose.
Acknowledgements
Edward F Chan, MD Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania School of Medicine
Edward F Chan, MD is a member of the following medical societies: American Academy of Dermatology, American Society of Dermatopathology, and Society for Investigative Dermatology
Disclosure: Nothing to disclose.
Michael J Wells, MD Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine
Michael J Wells, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, and Texas Medical Association
Bullous disease of diabetes (bullosis diabeticorum). Tense noninflammatory bulla on the leg.
Bullous disease of diabetes (bullosis diabeticorum). Unroofed blister on the leg. Note the irregular shape.
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).
Bullous disease of diabetes (bullosis diabeticorum). High-power view of the dermis beneath the blister showing capillary wall thickening (hematoxylin and eosin stain).
Bullous disease of diabetes (bullosis diabeticorum). Tense noninflammatory bulla on the leg.
Bullous disease of diabetes (bullosis diabeticorum). Unroofed blister on the leg. Note the irregular shape.
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).
Bullous disease of diabetes (bullosis diabeticorum). High-power view of the dermis beneath the blister showing capillary wall thickening (hematoxylin and eosin stain).
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