Bullosis diabeticorum(BD) is a cutaneous complication in patients with diabetes mellitus, which even could precede the diagnosis of diabetes mellitus and be suggested to be probable cutaneous markers for early detection of overt diabetes or prediabetes. The first case of bullosis diabeticorum was reported by Kramer in 1930. Cantwell and Martz further first coined the term “Bullosis Diabeticorum” in 1967, and this remains the common nomenclature today[3, 5]. BD is characterized by spontaneously formed bullae, without pain, trauma or any signs of inflammation. The blisters of BD often suddenly appear overnight, sometimes within 1 hour without any obvious cause, no recent trauma, and rarely cause slight discomfort. Sometimes the blisters are large, with irregular borders and looseness, very similar to burn lesions. And the bulla are full of serum and rarely bleed[6, 7]. Typical blisters are superficial and contain transparent sterile liquids[8]. Blisters usually heal within 2–6 weeks, without scarring. And three-year follow-up survey of 25 patients with BD showed that the median healing time was 2.5 months[6]. But there is a high chance of recurrence in the same or different body parts. Although bullous lesions are usually cured without scarring, they often turn into ulcers[3]. BD of the feet may turn into severe chronic ulcers, accompanied by skin necrosis and infection. It is reported that skin manifestations are associated with a significant incidence of diabetic foot ulcers[9, 10]. The association between osteomyelitis and BD also has been reported, leading to a high rate of amputation [11, 12]. Special attention should be paid to the prevention of high-risk patients.
BD is often described in adults from 34 to 91 years of age, mostly in males (male to female ratio: 2 to 1), with acute onset and bullous formation, which is similar to our findings. In our research, BD shows a higher frequency in males, also with a male-to-female ratio of 2:1. Studies have estimated that the prevalence among patients with diabetes is between 0.16% and 2%[6]. One of the reasons for the underestimated situation is that patients with BD lack the awareness of seeking medical attention and healing automatically. Some researchers suspect that this situation is more common than people generally believed[11]. In our clinical experience and observation, BD is not uncommon, especially in patients with diabetic foot (DF). The exact incidence of BD has not yet been calculated. Among the 1506 patients with diabetes included in this study, 602 had BD. Thus, there was a BD incidence rate of 39.97% in patients with diabetes. Many cases of BD are described as patients with diabetes exposed to ultraviolet light without any trauma, or diabetic patients with kidney disease, microangiopathy and long-term uncontrolled diabetes[11]. And BD can occur in patients with pre-diabetes, even in patients with good glycemic control (type 1 or type 2 diabetes)[13, 14]. Some researchs have noticed that their patients have neuropathy, but this is not universal[6, 15].
Calcium and magnesium imbalances, adverse reactions of modern diabetes drugs or immune vasculitis are also considered important factors[6–8] [16, 17]. There is no literature describing the correlation between the occurrence of BD and the clinical indicators of diabetic patients. And no formal diagnosis and treatment guidelines exist now. Understanding the risk factors for BD can help clinicians take prompt action and take preventive measures in a timely manner, and prevents the formation of chronic ulcers. In this observational study, we examined the association between clinical parameters and BD. The present observational study demonstrated that higher BUA but not eGFR, was significantly and positively associated with the prevalence of BD in patients with diabetes, suggesting higher BUA as a definite risk for BD, independent of other risk factors for BD, such as age, HbA1c, SCr, Cys-C, eGFR, etc. Eunsung Kim and his colleagues found that elevated SUA levels are independently associated with the presence of ulcers, thereby suggesting the potential role of hyperuricemia in the pathogenesis of vasculopathy[18]. Another research indicates SUA as a marker of microvascular damage[19]. Therefore, elevated SUA may lead to the occurrence of DB by affecting microvascular lesions, but further research is needed to confirm that. Glucose control does not seem to be directly related to the formation of bullae. Bernstein and his colleagues concluded that cation imbalance caused by renal failure may be a possible cause of BD[8]. But these were not be found in our research. Vesicular fluid usually contains protein and may contain eosinophils or a small number of polymorphonuclear cells[17, 20]. M. Derighetti reported that histopathological examination of BD showed microvascular disease with degeneration of the vessel wall[21].
It is thought BD is related to insufficient blood vessel supply and increased vascular pressure, resulting in the epidermal-dermal junction dividing at the level of the hyaluronic membrane. Some authors speculate that its etiology may be related to local connective tissue changes in the subbasement membrane area. Some patients have a skin separation level within the epidermis, while others have a skin separation level below the epidermis[15]. Histological examination showed that C3, IgM, IgA and IgG were negative by direct immunofluorescence (DIF) staining[17]. This is different from hemorrhagic bullae, which show atrophy and scarring after healing; these manifest as the destruction of the cleavage surface and anchored fibrils below the junction of the dermal epidermis. Histopathological examination of BD showed inconsistent degrees of skin separation. In most published cases, there is cleavage in the epidermis without lysis of spinous cells[22]. Some studies on BD have reported mild or thickened skin papillary blood vessels and focal deposition of capillary walls. Electron microscopy showed that the cell membrane and the basement membrane were separated, and before that, fixed filaments and hemi-desmosomes were lost. One study found no evidence that complement or immunoglobulin deposition, direct immunofluorescence and surrounding skin is normal[23].We recommend that extensive BD should be considered a limb-threatening condition. These patients require timely admission, the involvement of diabetes and foot care teams [24].
Recognition depends on the clinician's familiarity with this situation. There is no firm consensus on how to deal with these lesions[25]. It is recommended to treat non-infectious bullae with suction blisters to prevent spontaneous rupture, and use blistering skin as the wound cover[26]. If the bullous fluid has appeared cloudy, it may indicate that an infection has occurred, and it needs to be treated according to the DF treatment process. BD of feet require standard assessment and standard wound care procedures. The clinical manifestations of the lesions in these patients are similar to those reported previously. Our research reminds clinicians that BD is a skin disease that is not so rare and has a direct correlation with BUA. Our medical center saw more cases in a relatively short period of time. Little is known about the causes of BD. We observed that almost all of these blisters occurred on the skin parts without calluses, which indicates that these parts are not affected by high pressure. This typical skin disease is much more common than we know now. Any damage to the skin of the feet of diabetic patients may be the first step in amputation. Therefore, it is important to recognize this disease to ensure that appropriate treatment is provided to help avoid ulcers and infections [27–29]. Although there are some reports about BD, whether it is from the perspective of etiology or pathology, it is still poorly understood.