Links Between Granuloma Annulare,Necrobiosis Lipoidica Diabeticorum and Childhood Diabetes: A Matter of Time?

Abstract: Diabetes mellitus is associated with a range of dermatologic presentations, including granuloma annulare and necrobiosis lipoidica diabeticorum. Granuloma annulare occurs earlier than necrobiosis lipoidica diabeticorum and the association with diabetes mellitus is much weaker. We describe two children with diabetes who both developed granuloma annulare and later, necrobiosis lipoidica diabeticorum. We postulate that the early onset and transient nature of granuloma annulare, compared with the later onset and persistence of necrobiosis lipoidica diabeticorum, might account for the different apparent rates of association with diabetes mellitus.     

Granuloma Annulare, Necrobiosis Lipoidica, and Diabetic Disease

One hundred sixteen patients with granuloma annulare and necrobiosis lipoidica were studied. The relationship of these two disorders with diabetes mellitus suggests that atypical granuloma annulare could be linked to necrobiosis lipoidica, toward which it progresses.     

Serum alpha 2 globulin levels in granuloma annulare and necrobiosis lipoidica

Alpha 2-macroglobulin, caeruloplasmin and haptoglobin were measured in the sera of patients with necrobiosis lipoidica, granuloma annulare and diabetes. Alpha 2 Macroglobulin and caeruloplasmin were significantly raised in diabetes, and caeruloplasmin was raised in necrobiosis lipoidica without diabetes. The ratio of alpha 2-globulin to serum albumin was significantly high for all three proteins in diabetes, and for haptoglobin and caeruloplasmin in necrobiosis lipoidica. None of these proteins was abnormally raised in non-diabetic patients with granuloma annulare. There is good evidence that the plasma protein changes in diabetes contribute to the development of microangiopathy by their influence on blood viscosity. The altered plasma protein profile in necrobiosis lipoidica may therefore be of relevance to the development of the vascular lesions in this disorder.     

Simultaneous occurrence of ulcerated necrobiosis lipoidica and granuloma annulare in a patient: case report

Simultaneous occurrence of granuloma annulare and necrobiosis lipoidica is quite rare. There are seven reported cases in the literature, but only one presenting ulcerated necrobiosis lipoidica. We report a 39-year-old male with histopathologically confirmed granuloma annulare and ulcerated necrobiosis lipoidica, without diabetes mellitus.     

Serum beta-glucuronidase activity in human diabetes mellitus, granuloma annulare and necrobiosis lipoidica

Serum levels of β-glucuronidase, lysozyme and lactate dehydrogenase were measured in patients with granuloma annulare, necrobiosis lipoidica and diabetes mellitus and compared with levels in healthy controls. Significant elevation of serum levels of β-glucuronidase were observed in diabetes mellitus and granuloma annulare. β-Glucuronidase in necrobiosis lipoidica was not significantly different from the control group, although six out of twenty patients did show elevated enzyme levels. Serum lysozyme was not raised in any of the test groups, although a few sera from patients with severe lesions were found to be high. No difference in lactate dehydrogenase levels was observed between patient and control sera. The significance of these findings is discussed.     

Maturity-onset diabetes of the young with necrobiosis lipoidica and granuloma annulare

We describe a 12-year-old white girl with granuloma annulare localized to both ankles since she was five, necrobiosis lipoidica in the left pretibial region since she was ten, and a recent history of weakness, migraine, and weight loss. After initial evaluation, high fasting blood glucose levels and high hemoglobin A1c were found. The family history for non-insulin-dependent diabetes was suggestive of maturity-onset diabetes of the young. Coexistence of necrobiosis lipoidica and granuloma annulare, together with a family history of non-insulin-dependent diabetes, the age of onset, and the absence of ketosis, are specific features making possible, a clinical diagnosis. Genetic confirmation may not be so easily accessible or necessary.     

Lymphokines (MIF) in the serum of patients with sarcoidosis and cutaneous granuloma annulare

Serum MIF activity was studied in ten patients with sarcoidosis, fourteen with granuloma annulare, four with necrobiosis lipoidica, and nine with various dermatological diseases. Positive MIF activity was found in the sera of nine of the ten patients with sarcoidosis and eleven of the fourteen patients with granuloma annulare. The delayed hypersensitivity tests were negative in all nine of the patients with sarcoidosis who had serum MIF activity and were positive in only three patients with cutaneous sarcoid lesions. One of four patients with necrobiosis lipoidica demonstrated minimal serum MIF activity. Data on serum lymphokine activity in sarcoidosis and granuloma annulare suggest that these two diseases are related to delayed hypersensitivity mechanisms.     

Epidermal dendritic S100 positive cells in necrobiosis lipoidica and granuloma annulare

Using an antibody to S100 protein, the number of dendritic cells above the basal layer in the epidermis was assessed in necrobiosis lipoidica and granuloma annulare. A statistically significantly higher number of these cells was found within the epidermis in necrobiosis lipoidica compared with granuloma annulare and normal skin. The numbers were similar to those seen in sarcoidosis and tuberculous reactions in the skin, which raises the possibility of an immune pathogenesis for necrobiosis lipoidica.     

Necrobiosis lipoidica of the glans penis

We report a 65-year-old diabetic man with necrobiosis lipoidica occurring on the glans of penis. He was initially seen with chronic ulcerative balanitis that eventually healed with strict control of diabetes mellitus, cystostomy, and pentoxifylline, leaving heavily depressed scars. Penile necrobiotic palisading granulomas include necrobiosis lipoidica and granuloma annulare. On the basis of the literature review, these 2 diseases manifest different skin lesions.     

Necrobiosis lipoidica and sarcoidosis

We report the case of a female patient with necrobiosis lipoidica of the lower legs and coexistent systemic and cutaneous sarcoidosis. We review the six previously reported patients with coexisting necrobiosis lipoidica and sarcoidosis. The associations between the granulomatous disorders of the skin, especially necrobiosis lipoidica, sarcoidosis and granuloma annulare, are discussed. The common pathogenetic features of these disorders are reviewed.     

Increased factor VIII-related antigen in necrobiosis lipoidica and widespread granuloma annulare without associated diabetes

Factor VIII-related antigen was found to be raised in diabetics, and in patients with necrobiosis lipoidica and widespread granuloma annulare who were not diabetic. It was not increased in patients with solitary lesions of granuloma annulare. The relationship of factor VIII-related antigen to the development of micro-angiopathy in these conditions is discussed.     

Expression of the human erythrocyte glucose transporter Glut-1 in areas of sclerotic collagen in necrobiosis lipoidica

BACKGROUND: Glut-1 is the human erythrocyte glucose transporter which mediates facilitative transport of glucose across epithelial and endothelial barrier tissues. A primary abnormality in glucose transport and Glut-1 cell-surface content has been observed in fibroblasts from NIDDM and obese individuals. With the strong correlation between necrobiosis lipoidica and diabetes mellitus, we investigated the expression of Glut-1 in diabetic individuals with necrobiosis lipoidica (NL). METHODS: A polyclonal anti-Glut-1 antibody was used with a standard immunoperoxidase technique to determine Glut-1 expression by fibroblasts in areas of sclerotic collagen from specimens taken from diabetic individuals with necrobiosis lipoidica,and non-diabetic individuals with scars and granuloma annulare (GA). RESULTS: Our results showed Glut-1 expression in the areas of sclerotic collagen in patients with NL, possibly contributing to insulin resistance in these tissues. CONCLUSIONS: Our findings raises the question as to whether abnormalities in glucose transport by fibroblasts in individuals with necrobiosis lipoidica contribute to the histopathologic changes.     

Intracellular elastin in generalized granuloma annulare

This report reviews thirteen cases of generalized granuloma annulare. The light and electron microscopic appearance of intracellular elastin particles in eleven of these cases is described. These bodies were also noted in deep granuloma annulare, elastosis perforans serpiginosa, and a small percentage of localized granuloma annulare. They were not found in necrobiosis lipoidica.     

Glycosylated haemoglobin in patients with necrobiosis lipoidica and granuloma annulare

Glycosylated haemoglobin (HbA₁) content in the blood of twenty-two cases of necrobiosis lipoidica and fourteen cases of granuloma annulare were measured to see if it was elevated. Only eleven patients, all with known diabetes, had elevated HbA₁. These data support the concept that the microangiopathic changes in these two conditions occur independently of elevated blood glucose concentrations.     

Sweat gland disturbances in granuloma annulare and necrobiosis lipoidica

We studied sweat gland distribution, density and activity in thirteen cases of granuloma annulare and ten cases of necrobiosis lipoidica, using a combination of the plastic impression and starch-iodine methods. The pattern of sweat gland disturbance in the two diseases was entirely different. In necrobiosis lipoidica an intense and uniform hypohidrosis was detected throughout the lesion, whereas in granuloma annulare the disturbance followed the morphology of the lesion (the papular border showed complete anhidrosis, whereas the flat central part of the lesion showed only moderate hypohidrosis or normal sweating). The method assigns numerical values to the 'relative density' and the 'relative activity' of the functioning sweat glands compared with normal skin, thus permitting statistical evaluation of the results.     

Granuloma annulare and necrobiosis lipoidica treated by jet injector

A Porto-jet injector was employed to treat forty-five cases of granuloma annulare and five cases of necrobiosis lipoidica with triamcinolone acetonide or sterile normal saline. Complete clearance of granuloma annulare lesions was achieved in nearly 70% of those receiving triamcinolone and in 44% with saline. Inadequate penetration of lesions was responsible for a number of failures. The rate of recurrence after treatment was high but retreatment was usually successful. In three cases of necrobiosis lipoidica complete resolution occurred, while in one, partial improvement was obtained. No serious complications of this type of treatment were observed.     

Eosinophils in the cellular infiltrate of granuloma annulare

Eosinophils have been described in the infiltrates of granuloma annulare, but their frequency, distribution and extent are not well documented. We found eosinophils in 18/45 (40%) cases of granuloma annulare, without significant variation relating to histologic sub-pattern. Eosinophils were seen in over half the cases of deep granuloma annulare and in over one-third of the cases of superficial granuloma annulare. This study demonstrates the lack of specificity of eosinophils in differentiating superficial granuloma annulare from deep granuloma annulare, granuloma annulare from necrobiosis lipoidica, and granuloma annulare from occasional clinical simulants which histologically show eosinophils, such as arthropod bite reactions.     

Actinic granuloma (O'Brien)

Twelve cases of actinic graculoma (O'Brien) are reported. It is concluded that actinic granuloma is a specific disease characterized by clinical lesions indistinguishable from granuloma annulare, but occurring on solar damaged skin. Histologically, clastic tissue is destroyed by the granulomatous process in actinic granuloma. But not in granuloma annulare. It would appear that actinic granuloma, granuloma multiforme, necrobiosis lipoidica of the face and scalp (Wilson-Jones) and Miescher's granuloma of the face (Mehregan and Altman) are the same desease.     

Neutrophil mobility in granuloma annulare and necrobiosis lipoidica

Neutrophil mobility was investigated in thirteen cases of granuloma annulare and in twelve cases of necrobiosis lipoidica and found to be normal. Plasma from these patients did not inhibit the random or directed migration of neutrophils obtained from normal donors. The nature of the ‘in vivo’ defect of neutrophil migration previously reported in these conditions is at present unclear.