Background

Bullous disease of diabetes, or bullosis diabeticorum is a rare, spontaneous, noninflammatory blistering disorder affecting acral skin, and seen only in patients with diabetes mellitus. Bullous disease typically occurs in patients with long-standing diabetes, or multiple diabetic complications. The precise etiology remains unclear, and it has been reported in around 0.5% of diabetes patients in the United States, with men having double the incidence of women.

The condition was first reported by Kramer in 1930 and then Rocca and Pereyra reported their cases in 1963. Cantwell and Martz (1967) reported examples of recurrent, spontaneous blisters that formed on the extremities in patients with diabetes mellitus before formally describing the disease as bullosis diabeticorum.

Epidemiology

Bullous disease of diabetes (bullosis diabeticorum) is a very rare condition, with an established annual incidence of about 0.16% in those with diabetes. In the USA it has been found in approximately 0.5% of patients with diabetes, although its true prevalence is likely to be higher because of underreporting. This condition can occur in patients with newly diagnosed or uncomplicated diabetes, including type 2 diabetes, and in rare instances been reported in patients with prediabetes.

Anatomy

Pathophysiology

The pathophysiology of bullosis diabeticorum remains unclear and is likely multifactorial. Bernstein et al. showed that insulin-dependent diabetic patients had significantly less vacuum blister suction pressure than healthy age-matched controls (P < 0.01). The acral nature of the lesions has led to speculation about trauma as a contributing mechanism; however, this does not account for the lack of bullosis diabeticorum in most diabetic patients, the lack of trauma in many cases, and the spontaneous nature of recovery. Most patients have both nephropathy and neuropathy, and microangiopathy has been proposed as a potential mechanism, contributing to pre-mature aging of connective tissue, with localized effects within the subbasement membrane zone.

Etiology

The exact etiology of bullous disease of diabetes (bullosis diabeticorum) is unknown. The prominent acral distribution of lesions implies susceptibility to microtrauma; however, the majority of blisters develop spontaneously and without a report of any prior trauma. Many affected patients, but not all, have nephropathy or neuropathy; thus, some authors postulate a possible etiological association, and likely an association of localized changes in the connective tissue sub–basement membrane zone. The histological findings of small vessel hyalinosis have been suggested to indicate a possible contributory role of microangiopathy in the development of bullae. In some instances, especially in patients with neuropathy, contribution of ultraviolet (UV) exposure in the events leading to blister formation is also believed.

Genetics

Prognostic Factors

The bullous disease of diabetes (bullosis diabeticorum) blisters will usually heal spontaneously over 2–6 weeks. Secondary infection can occur, but the overall prognosis is usually good. Lesions generally resolve without considerable scarring, although it is common for lesions to come back and occasionally cause ulceration. Complications such as osteomyelitis or amputation from infection are rare.

Clinical History

Age group

Bullous disease of diabetes (bullosis diabeticorum) typically occurs in patients from 17-84 years of age although it has been reported in children as early as three years of age in unusual cases. The disease has been described as more common in males than females (2:1). Bullous disease of diabetes is overall a rare but clinically recognizable complication of diabetes that predominantly occurs in adult men with long-standing poorly controlled diabetes. It can also be seen in adults in which the diagnosis of diabetes was newly diagnosed or simple cases of diabetes. In very rare cases, bullous disease of diabetes has been described in prediabetes.

Physical Examination

The majority of bullosis diabeticorum patients have a history of longstanding diabetes; however, the disorder may be found in both insulin-dependent and noninsulin-dependent diabetes mellitus.

Many of the affected individuals have diabetic complications in association (for example, polyneuropathy, retinopathy, or nephropathy), with bullae at times being the first presenting feature.

The goal of the physical examination is to assess the location, size and properties of the lesions, while educating a working differential diagnosis. A skin biopsy may sometimes be required to make the definitive diagnosis, and cultures may be taken to assess for secondary infections that would require treatment.

Age group

Associated comorbidity

Bullous disease of diabetes (bullosis diabeticorum) tends to occur in long-standing diabetes and is frequently associated with diabetic complications such as neuropathy or nephropathy. Other potential factors include microangiopathy, changes in the local connective tissue, and, in some cases, minor trauma or ultraviolet (UV) light. While most cases occur in longstanding complicated diabetes, they can occur in patients with newly diagnosed or uncomplicated diabetes, and exceptionally, even in someone with prediabetes.

Associated activity

Acuity of presentation

Bullosis diabeticorum has been reported in a few cases, as the first presentation of prediabetes when glucose tolerance is impaired. Disturbances in calcium, magnesium and carbohydrate metabolism have also been proposed as factors in some cases. Exposure to excessive ultraviolet (UV) light, especially in nephropathic patients, may contribute in some cases. Further, patients who are in end stage renal failure may have mildly elevated plasma porphyrin levels, which might also contribute to blister development.

Differential Diagnoses

Bullous pemphigoid

Friction blisters or traumatic bullae

Epidermolysis bullosa

Porphyria cutanea tarda

Pemphigus vulgaris

Infectious bullous lesions

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Staging

Treatment Paradigm

Elevation of the blister: Keep intact bullae undisturbed to act as a natural, sterile cover.

Infection control: Early identification and treatment of secondary infections with appropriate antibiotics.

Drainage of blisters: When necessary, needle aspiration or a small window can be made in the roof of the blister, and then topical antiseptics or antibiotics can be applied to reduce discomfort and prevent infection.

Wound care: For unroofed blisters, aggressive care like that with diabetic ulcers, including debridement or tissue grafting for necrotic tissue.

by Stage

by Modality

Chemotherapy

Radiation Therapy

Surgical Interventions

Hormone Therapy

Immunotherapy

Hyperthermia

Photodynamic Therapy

Stem Cell Transplant

Targeted Therapy

Palliative Care

role-of-environmental-modifications-in-treating-bullous-disease-of-diabetes

Immobilization and offloading: Protect areas from trauma and pressure.

Reduce UV exposure: Especially important in patients with neuropathy or nephropathy.

Optimize glycemic control: Relative stabilization of blood glucose may decrease recurrence rate and will improve overall health of skin.

Monitoring comorbidities: These complicating factors should be monitored closely and managed, all diabetic complications (including neuropathy, nephropathy, and retinopathy) should be reviewed and limited these effects affecting skin health.

role-of-intervention-with-procedure-in-treating-bullous-disease-of-diabetes

Aspiration and Debridement:

The fluid from lesions of bullosis diabeticorum may be aspirated through a sterile small-bore needle to avoid unintentional rupture. Immobilization of the affected area is helpful to protect the blister from trauma. Removal of necrotic tissue and grafting may be indicated in the case of secondary tissue necrosis. If a blister erodes (unroofed), aggressive wound care like that used for diabetic ulcers is required. Patients need to be monitored for secondary infections until the lesions have healed completely.

role-of-management-in-treating-bullous-disease-of-diabetes

There is no clear agreement on the approach of bullosis diabeitocorum. The blisters are typically self-limiting, healing in 2-6 weeks without any treatment. Most experts recommend that the blister be left alone as the overlying skin wound closure will maintain a sterile environment. Antibiotic treatment is only needed if a subsequent staphylococcal infection develops. Some physicians advocate small-bore needle aspiration or small windshield in the blister roof and either topical antiseptics or topical antibiotics to follow to provide patient comfort, and to prevent infection. If an underlying soft tissue infection develops, surgical intervention may be necessary due to bone concerns (e.g. osteomyelitis). To provide protection for the blister, immobilization may be helpful. Secondary issues (e.g. tissue necrosis or redness) cause tissue necrosis may require debridement or subsequent grafting. If the blister roof is unroofed, aggressive wound care like the treatment of diabetic ulcers is necessary. In the event of repeated reoccurrence, autologous bone marrow mesenchymal cell transplant therapy has been documented to be a successful therapeutic alternative.

Medication

Future Trends

Media Gallary

References

Bullosis Diabeticorum – StatPearls – NCBI Bookshelf