Continuing Education Activity

This comprehensive course focuses on bullous disease of diabetes, also recognized as bullosis diabeticorum. This unique blistering disorder spontaneously affects the skin of the extremities in individuals with diabetes mellitus, particularly those with longstanding disease. Although the exact etiology remains unknown, the condition is not associated with inflammation. Throughout this activity, learners explore the pathophysiology and presentation of bullous diabeticorum. The course covers the specific characteristics of this disorder, shedding light on its manifestations on the skin of the extremities in individuals with diabetes mellitus. An emphasis is on understanding the unique features that differentiate bullous diabeticorum from other skin conditions. This course addresses the crucial aspect of managing bullous diabeticorum. The importance of leaving blistered skin intact as an effective and sterile cover for underlying wounds is discussed. Learners gain insights into the rationale behind these interventions and their potential impact on patient outcomes.

A significant highlight of this course is the emphasis on the role of the interprofessional team in the management of bullous diabeticorum. By engaging in collaborative discussions and case studies, learners understand how professionals from diverse fields, including dermatologists, endocrinologists, nurses, and wound care specialists, contribute to comprehensive patient care.

Objectives:

• Identify the characteristic clinical features and presentation of bullosis diabeticorum in individuals with diabetes mellitus.
• Differentiate bullosis diabeticorum from other skin disorders with similar manifestations, ensuring accurate diagnosis and targeted treatment.
• Evaluate the severity and progression of bullosis diabeticorum, utilizing standardized assessment tools to guide tailored treatment plans.
• Improve care coordination among interprofessional team members to improve outcomes for affected patients.

Introduction

Bullosis diabeticorum, also known as diabetic bullae or bullous eruption of diabetes mellitus, is a specific type of skin lesion exclusively occurring in patients with diabetes mellitus. Kramer first described the condition in 1930, and Rocca and Pereyra later described this in 1963. Cantwell & Martz noticed the recurrent spontaneous blisters on the extremities of patients with diabetes mellitus and introduced the label “bullosis diabeticorum” in 1967.[1] Most affected individuals had longstanding diabetes mellitus with peripheral neuropathy. The skin lesions were asymptomatic and healed slowly without scarring in 2 to 6 weeks.[2]

Etiology

The etiology of bullosis diabeticorum is not known. While the majority of patients with the disease have associated diabetic nephropathy or neuropathy, some researchers have postulated a potential etiologic link that could be associated with a localized alteration in the connective tissue of the basement membrane zone secondary to microangiopathy. The observation of hyalinosis of small vessels in biopsy specimens has prompted some authorities to hypothesize that blister induction is associated with microangiopathy.[3] Imbalances of calcium and abnormal metabolism of carbohydrates also contribute to the disease.[2] Occasionally, the suspicion of immunological deposition arises as a potential cause of vasculopathy in patients who test positive for direct immunofluorescence. The purported significance of glycemic control has yet to be verified.[4][5]

Epidemiology

Bullosis diabeticorum is an uncommon condition, with a documented incidence of approximately 100 cases. The annual prevalence is about 0.16%.[3] Some reports say this condition manifests in around 0.5% of individuals with diabetes in the United States. However, the actual prevalence might be greater due to inadequate reporting of blistering cases in patients with diabetes. The condition usually occurs between 17 and 84 years, although there has been a recorded instance in a 3-year-old child.[6] The reported man-to-woman ratio of bullosis diabeticorum is 2:1 [7] and is found most frequently in adult men with longstanding uncontrolled diabetes.[8] Individuals who have uncomplicated or recently diagnosed diabetes may potentially experience the same effects. Occasionally, the condition has been documented in patients with prediabetes.

Pathophysiology

The pathophysiology of bullosis diabeticorum is not completely clear and appears to be multifactorial. In a study by Bernstein and colleagues, the authors demonstrated that patients with insulin-dependent diabetes have a markedly reduced threshold for suction blister development compared to age-matched normal controls, with a highly significant difference (P < 0.01).[9] Due to the acral prominence of bullosis diabeticorum in patients with diabetes mellitus, the role of trauma has been speculated. However, this cannot account for the absence of bullosis diabeticorum in the vast majority of those with diabetes, with the absence in most cases of any history of trauma and the fact that these lesions resolve spontaneously.[10] As the majority of patients with diabetes mellitus with bullosis diabeticorum have associated nephropathy and neuropathy, some have suggested the role of microangiopathy in the premature aging of connective tissue and, more precisely, a local subbasement membrane zone connective-tissue alteration.[11] 

Some individuals have presented with bullosis diabeticorum at first presentation of a prediabetic state with impaired glucose tolerance.[12] Moreover, the literature has postulated disturbances in calcium, magnesium, and carbohydrate metabolism are also contributory.[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 (see Image. Bullosis Diabeticorum Blister).[3]

Histopathology

The histologic findings are heterogeneous. Bullosis diabeticorum 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; recent publications have usually described subepidermal bullae.[13] The combinations of subepidermal and suprabasal bullae are not infrequent.[2] There have been suggestions that the cleavage level depends on the blister’s age. Bullae are initially subepidermal, progressing to intraepidermal blisters, representing older lesions undergoing re-epithelialization. The blister cavity contains clear, sterile proteinaceous fluid with little or no inflammation. However, the sub-epidermal variant can be hemorrhagic. The surrounding epidermis does not exhibit any major alteration. However, there have been occasional cases of concomitant spongiosis and degenerative keratinocytic pallor.[14] The dermis displays minimal inflammation other than microvascular changes consistent with diabetes.[2][15] Caterpillar bodies, often found in patients with porphyria, can also be seen.

Direct immunofluorescence examination is usually negative, although one report described non-specific associated immunoglobulin M and complement C3 deposits within dermal blood vessel walls.[4] The absence or reduction of anchoring fibrils and hemidesmosomes characterize early blisters.[2] Electron microscopy of fresh blisters has revealed separation in a subepidermal location, residing in the lamina lucida or below the lamina densa.

History and Physical

Bullosis diabeticorum characteristically starts with a sudden appearance of 1 or more painless, tense vesicles or bullae within normal-appearing, non-inflamed skin, generally on the acral portions of the body.[16] The most frequent locations reported in the literature are the tips of the toes and the plantar surface of the feet, distal legs, hands, and fore­arms.[13] Bullae are rarely present on the trunk, and the lesions are usually asymptomatic; however, some patients may occasionally notice a mild burning sensation. Blisters often develop spontaneously and in the absence of known trauma. The vesicles and bullae range from a few millimeters to several centimeters in size. Lesions typically start as tense blisters, which become flaccid and asymmetrical in shape as they enlarge and sometimes possess an uneven shape, resembling a burn. Blisters contain a clear and sterile fluid, which may sometimes be hemorrhagic; they can be filled with pus if there has been a secondary bacterial infection.

Most patients with bullosis diabeticorum have longstanding diabetes. Bullosis diabeticorum has associations with both insulin- 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.[13] The goals of the physical exam include finding the exact location and physical features of the lesions and coming up with a practical differential diagnosis. A biopsy may be required for an accurate diagnosis, and a culture may need to be collected to determine any secondary infections that require treatment.

Evaluation

Once the diagnosis of bullosis diabeticorum is considered, the patient should undergo evaluation for this metabolic condition, and their glycemic levels should be controlled. If diabetes mellitus is not a known diagnosis, perform a prompt screening. Patients with confirmed bullosis diabeticorum should be monitored for the development of secondary infections until lesions heal entirely.[17] Because of the higher prevalence of microangiopathic complications in patients with diabetes mellitus with bullosis diabeticorum, ophthalmological and neurological examinations are recommended. Evaluation of renal function, especially detecting microalbuminuria, is also necessary.

Treatment / Management

No firm consensus has emerged for managing bullosis diabeticorum.[18] The blisters have traditionally been deemed self-limiting, with bullae said to resolve if untreated within 2 to 6 weeks. Many authors have advised leaving the blistered skin intact since it constitutes an effec­tive and sterile cover for the underlying wound.[19] Drug therapy, specifically antibiotics, should only be used if there is a secondary staphylococcal infection. Some authors advocate a small-bore needle aspiration or placement of a small window in the blister roof and the application of topical antiseptics or antibiotics to reduce discomfort and prevent secondary infections. In some cases, surgical management of bullosis diabeticorum is required when soft tissue infection is present, given the significant risk of osteomyelitis.[18] Immobilization can help keep the blister safe. Secondary tissue necrosis may necessitate debridement and possible tissue grafting. Aggressive wound management, as with diabetic ulcers, is necessary should the blister become unroofed. Recurrent bullosis diabeticorum has undergone successful treatment with autologous bone marrow mesenchymal cell transplantation therapy.[20]

Differential Diagnosis

Several disorders should merit consideration in the differential diagnosis of bullosis diabeticorum. In porphyria cutanea tarda and pseudoporphyria, the blisters are usually infracentimetric and favor the hands rather than the feet and ankles, as in bullosis diabeticorum. Pseudoporphyria is not uncommon in patients with diabetes, as they may develop complications including both chronic renal failure and atherosclerotic cardio­vascular disease; they may be receiving dialysis or diuretics, which can produce pseudoporphyria. A patient with significant involvement of the back of the hands requires an assessment of their porphyrin levels. Individuals with the bullous illness of diabetes exhibit normal levels. Increased levels suggest the presence of porphyria cutanea tarda or another type of blistering porphyria. Patients suffering from end-stage renal disease may have slightly increased amounts of porphyrins in their blood plasma, potentially contributing to blister formation.

The distal extremity is a common site for erythema multiforme and fixed drug eruptions, but their bullae usually develop on an inflammatory base. The differential diagnosis also includes friction bullae, bullae due to burns or edema, bullous fixed drug reaction, bullous pemphigoid, and epidermolysis bullosa acquisita.[21] Epidermolysis bullosa acquisita and localized bullous pemphigoid closely resemble bullosis diabeticorum clinically and histologically. However, they can be distinguished from bullosis diabeticorum by histologic examination and direct immunofluorescence, as well as by the accen­tuation of lesions at frictional sites in patients with epidermolysis bullosa acquisita. Immunofluorescence investigations may be necessary to exclude related medical disorders such as bullous pemphigoid, epidermolysis bullosa acquisita, and porphyrias. These conditions often exhibit the accumulation of C3 and immunoglobulin G along the basement membrane zone.[22] Bullous cellulitis must also be considered if there is surrounding inflammatory skin with erythema, warmth, and tenderness. 

Prognosis

Bullosis diabeticorum 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 leading to ulceration and scarring [23] have been reported.[3] Bullous symptoms can reoccur over the years.

Complications

While lesions typically heal spontaneously within 2 to 6 weeks, they often recur in the same or different locations. Secondary infections characterized by cloudy blister fluid may develop and require a culture to verify and treat if indicated.[24] Additionally, there have been occurrences of osteomyelitis occurring at a location where the bullous disease of diabetes is present.[25] There are also reports of amputations due to infection.[13][26]

Deterrence and Patient Education

All patients with diabetes should receive comprehensive education on preventive foot self-care. A thorough foot examination should encompass the examination of the skin, the evaluation of foot deformities, the assessment of neurological function, and the evaluation of vascular fitness, including the assessment of pulses in the legs and feet. Antibiotic medication is unnecessary for wounds with no signs of soft tissue or bone infection. Empiric antibiotic therapy can be explicitly directed at gram-positive cocci in acute infections.

Enhancing Healthcare Team Outcomes

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

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References

1.

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2.

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3.

Larsen K, Jensen T, Karlsmark T, Holstein PE. Incidence of bullosis diabeticorum--a controversial cause of chronic foot ulceration. Int Wound J. 2008 Oct;5(4):591-6. [PMC free article: PMC7951251] [PubMed: 19006577]

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Sonani H, Abdul Salim S, Garla VV, Wile A, Palabindala V. Bullosis Diabeticorum: A Rare Presentation with Immunoglobulin G (IgG) Deposition Related Vasculopathy. Case Report and Focused Review. Am J Case Rep. 2018 Jan 15;19:52-56. [PMC free article: PMC5776741] [PubMed: 29332930]

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Chiriac A, Costache I, Podoleanu C, Naznean A, Stolnicu S. Bullosis Diabeticorum in a Young Child: Case Report of a Very Rare Entity and a Literature Review. Can J Diabetes. 2017 Apr;41(2):129-131. [PubMed: 28017292]

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El Fekih N, Zéglaoui F, Sioud A, Fazaa B, Kharfi M, Gaigi S, Kamoun R. [Bullosis diabeticorum: report of ten cases]. Tunis Med. 2009 Nov;87(11):747-9. [PubMed: 20209832]

9.

Bernstein JE, Levine LE, Medenica MM, Yung CW, Soltani K. Reduced threshold to suction-induced blister formation in insulin-dependent diabetics. J Am Acad Dermatol. 1983 Jun;8(6):790-1. [PubMed: 6863644]

10.

Huntley AC. Threshold to suction-induced blister formation in insulin-dependent diabetics. J Am Acad Dermatol. 1984 Feb;10(2 Pt 1):305-6. [PubMed: 6715607]

11.

Braverman IM, Keh-Yen A. Ultrastructural abnormalities of the microvasculature and elastic fibers in the skin of juvenile diabetics. J Invest Dermatol. 1984 Mar;82(3):270-4. [PubMed: 6699427]

12.

Lopez PR, Leicht S, Sigmon JR, Stigall L. Bullosis diabeticorum associated with a prediabetic state. South Med J. 2009 Jun;102(6):643-4. [PubMed: 19434030]

13.

Lipsky BA, Baker PD, Ahroni JH. Diabetic bullae: 12 cases of a purportedly rare cutaneous disorder. Int J Dermatol. 2000 Mar;39(3):196-200. [PubMed: 10759959]

14.

Alhadyani A, DeVore A, Gaster E, Elston D. Pediatric patient with linearly distributed bullae. JAAD Case Rep. 2023 Sep;39:67-69. [PMC free article: PMC10450346] [PubMed: 37635858]

15.

Grillo VTRDS, Botelho MS, Lange EP, Secanho MS, de Camargo PAB, Miot HA. Bullosis diabeticorum as a differential diagnosis for limb ulcers: case report. J Vasc Bras. 2022;21:e20210190. [PMC free article: PMC9477478] [PubMed: 36187219]

16.

Wagner G, Meyer V, Sachse MM. [Bullosis diabeticorum : Two case studies]. Hautarzt. 2018 Sep;69(9):751-755. [PubMed: 29468278]

17.

Bello F, Samaila OM, Lawal Y, Nkoro UK. 2 Cases of Bullosis Diabeticorum following Long-Distance Journeys by Road: A Report of 2 Cases. Case Rep Endocrinol. 2012;2012:367218. [PMC free article: PMC3479936] [PubMed: 23119191]

18.

Shahi N, Bradley S, Vowden K, Vowden P. Diabetic bullae: a case series and a new model of surgical management. J Wound Care. 2014 Jun;23(6):326, 328-30. [PubMed: 24920203]

19.

Kansal NK, Anuragi RP. Bullous lesions in diabetes mellitus: bullous diabeticorum (diabetic bulla). BMJ Case Rep. 2020 Aug 27;13(8) [PMC free article: PMC7454193] [PubMed: 32859620]

20.

Chen Y, Ma Y, Li N, Wang H, Chen B, Liang Z, Ren R, Lu D, Boey J, Armstrong DG, Deng W. Efficacy and long-term longitudinal follow-up of bone marrow mesenchymal cell transplantation therapy in a diabetic patient with recurrent lower limb bullosis diabeticorum. Stem Cell Res Ther. 2018 Apr 10;9(1):99. [PMC free article: PMC5891952] [PubMed: 29631615]

21.

Taylor SP, Dunn K. Bullosis Diabeticorum. J Gen Intern Med. 2017 Feb;32(2):220. [PMC free article: PMC5264667] [PubMed: 27400924]

22.

Hines A, Alavi A, Davis MDP. Cutaneous Manifestations of Diabetes. Med Clin North Am. 2021 Jul;105(4):681-697. [PubMed: 34059245]

23.

Vangipuram R, Hinojosa T, Lewis DJ, Downing C, Hixson C, Salas-Alanis JC, Tyring SK. Bullosis Diabeticorum: A Neglected Bullous Dermatosis. Skinmed. 2018;16(1):77-79. [PubMed: 29551123]

24.

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25.

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26.

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Disclosure: Chourouk Chouk declares no relevant financial relationships with ineligible companies.

Disclosure: Noureddine Litaiem declares no relevant financial relationships with ineligible companies.