Bullosis Diabeticorum

Article Author:
Chourouk Chouk

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Noureddine Litaiem

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Phillip Hynes

5/18/2019 10:29:16 PM


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 diabetic patients. 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]


The pathophysiology of BD is not completely clear and appears to be multifactorial. In a study of Bernstein and colleagues, authors demonstrated that insulin-dependent diabetics have a marked reduced threshold to suction blister development as compared to age-matched normal controls, with a highly significant difference (p<0.01).[3] And because of the acral prominence of BD in diabetic patients, 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 diabetic patients 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] The 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]


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 diabetic patients, 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]


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]


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 diabetic patients with BD, ophthalmological and neurological examination 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 as 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. Surgical management of BD was required in some cases, 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.


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 primary care provider, nurse practitioner, internist, and endocrinologist. The connection between BD and the degree of glycaemic 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.

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Bullosis Diabeticorum - Questions

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The characteristic blisters of bullosis diabeticorum are most likely to appear on what part of the body?

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A 65-year-old patient with diabetes mellitus and chronic renal failure presented with a single large, tense blister on the heel. The blister arose on a non-inflamed base. What is the most likely diagnosis?

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Bullosis Diabeticorum - References


Bullosis Diabeticorum: A Neglected Bullous Dermatosis., Vangipuram R,Hinojosa T,Lewis DJ,Downing C,Hixson C,Salas-Alanis JC,Tyring SK,, Skinmed, 2018     [PubMed]
[Bullosis diabeticorum : Two case studies]., Wagner G,Meyer V,Sachse MM,, Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandte Gebiete, 2018 Sep     [PubMed]
Bullosis Diabeticorum: A Rare Presentation with Immunoglobulin G (IgG) Deposition Related Vasculopathy. Case Report and Focused Review., Sonani H,Abdul Salim S,Garla VV,Wile A,Palabindala V,, The American journal of case reports, 2018 Jan 15     [PubMed]
Cantwell AR Jr,Martz W, Idiopathic bullae in diabetics. Bullosis diabeticorum. Archives of dermatology. 1967 Jul;     [PubMed]
Toonstra J, Bullosis diabeticorum. Report of a case with a review of the literature. Journal of the American Academy of Dermatology. 1985 Nov;     [PubMed]
Bernstein JE,Levine LE,Medenica MM,Yung CW,Soltani K, Reduced threshold to suction-induced blister formation in insulin-dependent diabetics. Journal of the American Academy of Dermatology. 1983 Jun;     [PubMed]
Huntley AC, Threshold to suction-induced blister formation in insulin-dependent diabetics. Journal of the American Academy of Dermatology. 1984 Feb;     [PubMed]
Braverman IM,Keh-Yen A, Ultrastructural abnormalities of the microvasculature and elastic fibers in the skin of juvenile diabetics. The Journal of investigative dermatology. 1984 Mar;     [PubMed]
Lopez PR,Leicht S,Sigmon JR,Stigall L, Bullosis diabeticorum associated with a prediabetic state. Southern medical journal. 2009 Jun;     [PubMed]
Larsen K,Jensen T,Karlsmark T,Holstein PE, Incidence of bullosis diabeticorum--a controversial cause of chronic foot ulceration. International wound journal. 2008 Oct;     [PubMed]
El Fekih N,Zéglaoui F,Sioud A,Fazaa B,Kharfi M,Gaigi S,Kamoun R, [Bullosis diabeticorum: report of ten cases]. La Tunisie medicale. 2009 Nov;     [PubMed]
Gupta V,Gulati N,Bahl J,Bajwa J,Dhawan N, Bullosis diabeticorum: rare presentation in a common disease. Case reports in endocrinology. 2014;     [PubMed]
Lipsky BA,Baker PD,Ahroni JH, Diabetic bullae: 12 cases of a purportedly rare cutaneous disorder. International journal of dermatology. 2000 Mar;     [PubMed]
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 reports in endocrinology. 2012;     [PubMed]
Shahi N,Bradley S,Vowden K,Vowden P, Diabetic bullae: a case series and a new model of surgical management. Journal of wound care. 2014 Jun;     [PubMed]
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 research     [PubMed]


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