eMedicine Specialties > Dermatology > Bullous Diseases

Bullous Disease of Diabetes

Jacqueline M Junkins-Hopkins, MD, Associate Professor, Director, Division of Dermatopathology and Oral Pathology, Department of Dermatology, Johns Hopkins Medical Institutions

Updated: Jun 24, 2009

Introduction

Background

Bullous disease of diabetes (bullosis diabeticorum) is a distinct, spontaneous, noninflammatory, blistering condition of acral skin unique to patients with diabetes mellitus. Kramer first reported bullouslike lesions in diabetic patients in 1930^{[1 ]}; Rocca and Pereyra first characterized this as a phlyctenar (appearing like a burn-induced blister) in 1963.^{[2 ]}Cantwell and Martz are credited with naming the condition, bullous diabeticorum, in 1967.^{[3 ]}It is also termed bullous disease of diabetes and diabetic bullae.

Also see the eMedicine articles Diabetes Mellitus, Type 1 and Diabetes Mellitus, Type 2.

Pathophysiology

The etiology of bullous disease of diabetes (bullosis diabeticorum) is not known. Patients with diabetes have been shown to have a lower threshold for suction-induced blister formation, and because of the acral prominence of diabetic bullae, the role of trauma has been speculated; however, this alone does not explain the often spontaneous development of multiple lesions at several locations. The pathophysiology is likely multifactorial.

Many, but not all, patients with bullous disease of diabetes (bullosis diabeticorum) have nephropathy or neuropathy; some authors have hypothesized an etiologic association, possibly related to a local, subbasement, 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, the blisters are related to UV exposure, especially in patients with nephropathy.^{[4 ]}Glycemic control does not appear to have a direct correlation with blister formation.

Some electron microscopic evidence has suggested an abnormality in anchoring fibrils. A reduced threshold to suction-induced blister formation in diabetic persons as compared with nondiabetic controls has been reported.^{[5 ]}Prominent acral accentuation of these lesions suggests a susceptibility to trauma-induced changes, but the definitive explanation awaits elucidation.

Frequency

United States

Bullosis diabeticorum tends to arise in patients with long-standing diabetes mellitus or with multiple complications of the disease. Bullous disease of diabetes has been reported to occur in approximately 0.5% of diabetic patients. The frequency may be higher because the occurrence of blistering is likely under-reported. Patients with uncomplicated or newly diagnosed disease, including type 2 diabetes, also may be affected.

Mortality/Morbidity

Bullous disease of diabetes lesions often heal without significant scarring, but they may be recurrent and may lead to ulceration.^{[4 ]}One report has described osteomyelitis arising at a site of bullosis diabeticorum.^{[6 ]}In a reported series of 12 patients with diabetic bullae, one required amputation because of infection.^{[7 ]}

Sex

A male-to-female ratio of 2:1 is reported in the literature for bullous disease of diabetes.

Age

The reported age of onset of bullous disease of diabetes ranges from 17-84 years.

Clinical

History

• Bullous disease of diabetes blisters occur spontaneously and abruptly, often over night, and usually without known antecedent trauma.
• Bullous disease of diabetes lesions tend to be asymptomatic, although mild discomfort or burning has been described.
• Bullous disease of diabetes blisters heal spontaneously within 2-6 weeks of onset.

Physical

• Bullous disease of diabetes (bullosis diabeticorum) manifests as tense, nontender blisters arising on nonerythematous skin. Some blisters may be flaccid.
• Bullous disease of diabetes blisters typically occur on the feet or lower legs (see Media File 1), but they also may occur on fingers, toes, hands, and arms.

Tense noninflammatory bulla on the leg.

• Bullous disease of diabetes blisters tend to be large (from 0.5-17 cm in diameter), often with an irregular shape (see Media File 2), simulating a burn.

Unroofed blister on the leg. Note the irregular shape.

• Rarely, nonacral sites (eg, trunk) may be involved.

Causes

• Prominent acral accentuation of bullous disease of diabetes lesions suggests a susceptibility to trauma-induced changes, but the definitive explanation awaits elucidation. Neuropathology, UV exposure, and microangiopathy associated with diabetes also are thought to play a role.

Differential Diagnoses

Other Problems to Be Considered

Blistering distal dactylitis

Workup

Laboratory Studies

• Consider evaluation of porphyrin levels if lesions prominently involve the hands. Elevated levels may indicate porphyria cutanea tarda.Levels reportedly are normal in persons with bullous disease of diabetes (bullosis diabeticorum).
• If the bullous disease of diabetes blister fluid is cloudy instead of clear, consider excluding secondary bacterial infection with culture of the blister fluid.

Other Tests

• Immunofluorescence: No primary immunologic abnormality is noted. Nonspecific capillary-associated immunoglobulin M and C3 have been reported rarely.^{[8 ]}Immunofluorescence findings have not been consistently reproduced by others, and direct immunofluorescence findings are usually negative.^{[9 ]}This study may be required to exclude clinically similar conditions (eg, bullous pemphigoid, epidermolysis bullosa acquisita) that typically show deposition of C3 and immunoglobulin G along the basement membrane zone.

Procedures

• Skin biopsy
  • Consider shave biopsy or excisional/incisional biopsy to help distinguish bullous disease of diabetes (bullosis diabeticorum) from clinically similar conditions.
  • For routine histologic sections, include the blister and portions of the underlying dermis in the biopsy specimen, and submit it in formalin. For biopsy findings, see Histologic Findings below.
  • Histologic features of bullosis diabeticorum are not entirely specific; consider direct immunofluorescence studies to exclude histologically similar entities (eg, noninflammatory bullous pemphigoid, epidermolysis bullosa acquisita, porphyria cutanea tarda). Include perilesional uninvolved skin in biopsy for direct immunofluorescence and submit it in special transport medium (eg, Michel).

Histologic Findings

Lesions of bullous disease of diabetes (bullosis diabeticorum) have a heterogeneous histologic presentation. The blister plane may appear in a subcorneal, intraepidermal, or subepidermal location. Histology of fresh blisters tends to show an epidermal-dermal separation (see Media File 3).

Histology of bullosis diabeticorum showing a noninflammatory blister with a subepidermal and focally intraepidermal separation (hematoxylin and eosin stain).

Many of the reported cases describe a separation in the superficial epidermis, within the superficial part of the spinous layer. 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 Media File 4). Caterpillar bodies typical of porphyria have been reported in lesions of bullosis diabeticorum.

High-power view of the dermis beneath the blister showing capillary wall thickening (hematoxylin and eosin stain).

Treatment

Medical Care

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. Secondary staphylococcal infections may occur, requiring antibiotic therapy.

Helpful guidelines from the American Diabetes Association related to the management of diabetes are as follows:

• Nutrition recommendations and interventions for diabetes: a position statement of the American Diabetes Association^{[11 ]} 
• Standards of medical care in diabetes. I. Classification and diagnosis^{[12 ]} 
• Standards of medical care in diabetes. V. Diabetes care.^{[13 ]}

Surgical Care

Aspiration of fluid from bullous disease of diabetes (bullosis diabeticorum) lesions with sterile technique using a small-bore needle may be beneficial to prevent accidental rupture. Immobilization may prevent damage to the blister. Secondary tissue necrosis may necessitate debridement and possible tissue grafting.

Follow-up

Further Outpatient Care

• Monitor bullous disease of diabetes (bullosis diabeticorum) patients for development of secondary infection.
• Exclude other blistering dermatoses.
• Immediately address unroofed blisters, and institute the appropriate wound-healing treatment regimen.

Complications

• Secondary infection and occasional scarring may occur with bullous disease of diabetes (bullosis diabeticorum).
• Osteomyelitis reportedly has developed at a site of bullous disease of diabetes (bullosis diabeticorum).
• The need for amputation due to secondary infection has been reported.

Prognosis

• The bullous disease of diabetes (bullosis diabeticorum) blisters typically heal spontaneously, within 2-6 weeks, but lesions often recur in the same or a different location.
• Secondary infection may develop, but the prognosis for bullous disease of diabetes (bullosis diabeticorum) typically is good.

Patient Education

• For excellent patient education resources, visit eMedicine's Diabetes Center.

Miscellaneous

Medicolegal Pitfalls

• Failure to recognize bullous disease of diabetes (bullosis diabeticorum) may result in the overzealous treatment or systemic evaluations that may be required for similar conditions, such as porphyria or epidermolysis bullosa acquisita.

Multimedia

Media file 1: Tense noninflammatory bulla on the leg.

Media file 2: Unroofed blister on the leg. Note the irregular shape.

Media file 3: Histology of bullosis diabeticorum showing a noninflammatory blister with a subepidermal and focally intraepidermal separation (hematoxylin and eosin stain).

Media file 4: High-power view of the dermis beneath the blister showing capillary wall thickening (hematoxylin and eosin stain).

References

1. Kramer DW. Early or warning signs of impending gangrene in diabetes. Med J Rec. 1930;132:338-42.

2. Rocca FF, Pereyra E. Phlyctenar lesions in the feet of diabetic patients. Diabetes. May-Jun 1963;12:220-2. [Medline].

3. Cantwell AR Jr, Martz W. Idiopathic bullae in diabetics. Bullosis diabeticorum. Arch Dermatol. Jul 1967;96(1):42-4. [Medline].

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

5. 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. Jun 1983;8(6):790-1. [Medline].

6. Tunuguntla A, Patel KN, Peiris AN, Zakaria WN. Bullosis diabeticorum associated with osteomyelitis. Tenn Med. Nov 2004;97(11):503-4. [Medline].

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

8. James WD, Odom RB, Goette DK. Bullous eruption of diabetes mellitus. A case with positive immunofluorescence microscopy findings. Arch Dermatol. Oct 1980;116(10):1191-2. [Medline].

9. Basarab T, Munn SE, McGrath J, Russell Jones R. Bullosis diabeticorum. A case report and literature review. Clin Exp Dermatol. May 1995;20(3):218-20. [Medline].

10. Toonstra J. Bullosis diabeticorum. Report of a case with a review of the literature. J Am Acad Dermatol. Nov 1985;13(5 Pt 1):799-805. [Medline].

11. [Guideline] Bantle JP, Wylie-Rosett J, Albright AL, et al. Nutrition recommendations and interventions for diabetes: a position statement of the American Diabetes Association. Diabetes Care. Jan 2008;31 Suppl 1:S61-78. [Medline].

12. [Guideline] American Diabetes Association. Standards of medical care in diabetes. I. Classification and diagnosis. Diabetes Care. Jan 2008;31(Suppl 1):S12-3.

13. [Guideline] American Diabetes Association. Standards of medical care in diabetes. V. Diabetes care. Diabetes Care. Jan 2008;31(Suppl 1):S16-24.

14. Bernstein JE, Medenica M, Soltani K, Griem SF. Bullous eruption of diabetes mellitus. Arch Dermatol. Mar 1979;115(3):324-5. [Medline].

15. Centers for Disease Control and Prevention. National Diabetes Fact Sheet. United States. Atlanta, Ga: Centers for Disease Control and Prevention; 2003:[Full Text].

16. Goodfield MJ, Millard LG, Harvey L, Jeffcoate WJ. Bullosis diabeticorum. J Am Acad Dermatol. Dec 1986;15(6):1292-4. [Medline].

17. Phillips P, Weightman W. Diabetes and the skin. Correspondence. Aust Fam Physician. Oct 2005;34(10):48.

Keywords

bullous disease of diabetes, bullosis diabeticorum, diabetic bullae, diabetes mellitus, diabetic disease, type 1 diabetes, insulin-dependent diabetes, diabetes complications, uncomplicated diabetes, type 2 diabetes

Contributor Information and Disclosures

Author

Jacqueline M Junkins-Hopkins, MD, Associate Professor, Director, Division of Dermatopathology and Oral Pathology, Department of Dermatology, Johns Hopkins Medical Institutions
Jacqueline M Junkins-Hopkins, MD is a member of the following medical societies: American Academy of Dermatology, American College of Physicians, and American Society of Dermatopathology
Disclosure: Nothing to disclose.

Medical Editor

Maureen B Poh-Fitzpatrick, MD, Professor Emerita of Dermatology and Special Lecturer, Columbia University; Professor of Medicine (Dermatology), University of Tennessee
Maureen B Poh-Fitzpatrick, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, and New York Academy of Medicine
Disclosure: Nothing to disclose.

Pharmacy Editor

Michael J Wells, MD, Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center
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
Disclosure: Nothing to disclose.

Managing Editor

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.

CME Editor

Joel M Gelfand, MD, MSCE, Medical Director, Clinical Studies Unit, Assistant Professor, Department of Dermatology, Associate Scholar, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania
Joel M Gelfand, MD, MSCE is a member of the following medical societies: Society for Investigative Dermatology
Disclosure: AMGEN Consulting fee Consulting; AMGEN Grant/research funds None; Genentech Consulting fee Consulting; Centocor Consulting fee Consulting; Centocor Grant/research funds None; Covance Consulting fee Consulting; Shire  Consulting

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

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