Necrobiosis lipoidica

Susannah Mc George1, Shernaz Walton2

1 Department of Dermatology, East Sussex Healthcare NHS Trust, UK
2 Department of Dermatology, Hull and East Yorkshire Hospitals NHS Trust and Hull York Medical School, Hull, UK

Address for correspondence: Dr Susannah George
Department of Dermatology,
Eastbourne District General Hospital, King’s Drive, Eastbourne,
East Sussex, BN21 2UD, UK
Tel: +44 (0)1323 417400 ext 3715

Br J Diabetes 2016;16:6-9


Necrobiosis lipoidica and granuloma annulare are granulomatous skin conditions that have been traditionally associated with diabetes mellitus, although recently the strength of association has been questioned. In the first section of this two-part article, we describe the suggested aetiology, clinical features, histology and treatment of necrobiosis lipoidica. It is found in 0.3% of patients with diabetes, but has also been reported with other systemic conditions. Clinically it appears as a waxy, atrophic, yellowish plaque with overlying telangi-ectasia and a brown border. Although usually asymptomatic, it may be extremely painful, especially if ulcerated. Squamous cell carcinoma has occasionally been reported with longstanding lesions. Treatment is often difficult: numerous topical and systemic agents have been employed, but evidence is limited to small case series and individual case reports.

Key words: necrobiosis lipoidica, diabetes, skin, dermatology


Necrobiosis lipoidica (NL) and granuloma annulare (GA) are histologically similar granulomatous skin conditions.1 Early reports suggested that NL may be a variant of GA, and it was not until the mid 20th century that recognition of subtle microscopic differences permitted classification as different conditions.2 Historically, they have been considered to be closely associated with diabetes mellitus; more recently the strength of the association has been questioned.3-5


While the similar histological appearances of GA and NL could potentially suggest the same predisposing factors, their clinical appearance is usually quite different and there are only a small number of case reports of the coexistence of the two conditions.1,2 Furthermore, Crosby et al argue that the subtle pathological, biochemical and immunological differences between the two conditions suggest different aetiologies.2

The aetiologies of NL and GA are unknown, although many theories have been proposed. The leading theory advocates that NL is a manifestation of microangiopathy resulting from glycoprotein deposition in blood vessel walls.6,7 Similar vascular changes involving glycoprotein deposition occur in diabetic microangiopathy of other organs, such as the eye and kidney, yet other microvascular complications of diabetes are relatively frequent and there is no evidence to suggest a shared aetiology with NL. Hypoxia has been suggested to play a role in the pathogenesis, however evidence for this is conflicting.7 Other possibilities include antibody-mediated vasculitis, collagen abnormalities, platelet aggregation, trauma, inflammatory and metabolic changes or a tumour necrosis factor mediated process.6,8 The finding of Glut 1 (human erythrocyte glucose transporter) expression in areas of sclerotic collagen suggest a possible role for abnormal glucose transport by fibroblasts.1

Association with diabetes

NL is more common in females than males and onset is most frequently in young adulthood or middle age.3,9,10 The average age of onset is 30 years in people with diabetes and 41 years in non- diabetic individuals.10 The age of onset is earlier in type 1 than type 2 diabetes.11 One early study found that up to 87% of patients with NL had diabetes at presentation.9 In the series reported by Muller and Winkelmann, 65% of patients with NL had diabetes at presentation with a positive family history of diabetes in 43% of diabetic and 26% of non-diabetic patients, respectively.10 However, Smith et al found that only 35% of patients with NL had diabetes.9 Dandona et al measured glycosylated haemoglobin in patients with GA and NL; although patients with known diabetes had elevated HbA1, patients with GA and NL who did not have diabetes had similar levels to controls.12 The authors concluded that in most cases the microangiopathic changes could not be due to hyperglycaemia or abnormal glucose tolerance and could not simply represent a reflection of hyperglycaemia. O’Toole et al found that only 11% of patients with NL were known to have diabetes at presentation, with a further 11% subsequently developing impaired glucose tolerance or diabetes.3 Two-thirds of patients with diabetes who develop NL have type 1 diabetes; however, only 0.3% of patients with diabetes develop NL.10,13 Large, recent series of patients attending diabetes clinics identified GA in 0–1.8% and NL in 0–1.4% of patients respectively.14-17

Traditionally, it has been thought that glycaemic control has no effect on the course of NL, however Cohen et al challenged this view following reappraisal of the original data and argued that tighter glycaemic control may prevent or ameliorate the condition.18 Furthermore, they suggest the possibility that NL may be a separate condition in people with and without diabetes.

NL has also been reported in association with sarcoidosis, inflammatory bowel disease, autoimmune thyroiditis, monoclonal gammopathy and in healthy individuals.7

Clinical features

Early lesions of NL present as well circumscribed erythematous papules or nodules that coalesce into plaques with a waxy, atrophic central area, with telangiectasia and an active red-brown border (Figures 1–3).6,7 They are usually painless, but may be exquisitely painful, especially if ulcerated (Figure 4). Lesions are most frequently located bilaterally on the lower extremities, but may occasionally occur at other sites (Figure 5).6,7 NL may Koebnerise, although this has rarely been reported.19 Ulceration may arise due to trauma and occurs in up to 35% of cases.10 Ulcerated lesions may be more common in patients with diabetes, than those without.9 Squamous cell carcinomas have occasionally been reported to complicate long-standing lesions.7,10,20,21,22

George Part 1, Figure 1

George Part 1, Firgure 2

George Part 1, Figure 3

George Part 1, Figure 4

George Part 1, Figure 5


The diagnosis of NL may be clinically obvious, although sometimes a skin biopsy is performed to confirm the diagnosis. Diagnosis of NL should prompt investigations for diabetes.


Histological examination of NL biopsy specimens reveals degeneration of collagen and interstitial and palisaded granulomas in the mid dermis consisting of multinucleated histiocytes, lymphocytes, plasma cells and eosinophils. Other features include extracellular lipid deposits, depletion of intradermal nerves and, in the mid to deep dermis, thickening of blood vessel walls and endothelial cell swelling.4,6,13 The central yellow area is likely to be subcutaneous fat necrosis made visible by the thin dermis.4

George Part 1, Key messages


Treatment of NL, and ulcerated lesions in particular, is often difficult.23 Suspicion of early NL warrants referral to a dermatologist for diagnostic confirmation. Reid et al summarised the evidence for the various therapeutic approaches in a recent review.7 Optimising glycaemic control does not alter progression of the lesions. Therapeutic strategies involve avoiding trauma to minimise the risk of ulceration and treating infections with antiseptics or antibiotics. Many treatments have been described, with variable success, although evidence is limited to small trials and individual case reports. Topical or intralesional steroids can be applied to the active edge, with avoidance of the central atrophic area, which may be worsened by steroid use. Topical steroids and topical tretinoin have also been used in combination.24 Oral steroids25 and intravenous methylprednisolone26 have also been found to be effective. Improvement has been reported with topical calcineurin inhibitors,27 bovine collagen and intra-lesional infliximab. Systemic infliximab28 and other anti-TNF agents, etanercept,23 thalidomide and pioglitazone29 have been found to be helpful in individual cases. Suarez-Amor et al reviewed the literature on the use of biologics for NL, with success reported with infliximab, subcutaneous and intralesional etanercept in seven cases, six of which were ulcerated.23 Some improvement has been documented with anti-platelet agents (aspirin, dipyridamole and pentoxifylline). Other treatments described include nicotinic acid, ciclosporin, antimalarials, colchicine,30 clofazimine, mycophenolate mofetil, fumaric acid esters31 and intravenous immunoglobulin.26 Improvement has been reported following physical treatments, including psoralen combined with ultraviolet A,19 photodynamic therapy32 and CO2 laser. Berking et al reported complete response in 1/18 patients treated with photodynamic therapy with partial response in 6/18 and no response in the other 11.32 Surgical excision is not recommended for NL. The skin on the lower legs heals slowly and surgical treatment for any reason at this site may result in ulceration.

Ultimately NL remains a challenging condition to manage effectively and with no robust evidence base or guidelines to direct therapy, treatment choice will be influenced by clinical experience and patient comorbidities.

Conflict of interest None

Funding None


1.     Souza FH, Ribeiro CF, Pereira MA, Mesquita L, Fabrício L. Simultaneous occurrence of ulcerated necrobiosis lipoidica and granuloma annulare in a patient: case report. An Bras Dermatol 2011;86:1007-10.

2.     Crosby DL, Woodley DT, Leonard DD. Concomitant granuloma annulare and necrobiosis lipoidica. Report of a case and review of the literature. Dermatologica 1991;183:225-9.

3.     O'Toole EA, Kennedy U, Nolan JJ, Young MM, Rogers S, Barnes L. Necrobiosis lipoidica: only a minority of patients have diabetes mellitus. Br J Dermatol 1999;140:283-6.

4.     Ahmed I, Goldstein B. Diabetes mellitus. Clin Dermatol 2006;24:237-46.

5.     Thornsberry LA, English JC 3rd. Etiology, diagnosis, and therapeutic management of granuloma annulare: an update. Am J Clin Dermatol 2013;14:279-90.

6.     Barnes CJ, Davis L, Griffing GT, Butler DF, Chan EF, Raugi GJ. (Aug 22 2014) Necrobiosis Lipoidica,, Accessed: 25th January 2015

7.     Reid SD, Ladizinski B, Lee K, Baibergenova A, Alavi A. Update on necrobiosis lipoidica: a review of etiology, diagnosis, and treatment options. J Am Acad Dermatol 2013;69:783-91.

8.     Sehgal VN, Bhattacharya SN, Verma P. Juvenile, insulin-dependent diabetes mellitus, type 1-related dermatoses. J Eur Acad Dermatol Venereol 2011;25:625-36.

9.     Smith JG Jr. Necrobiosis lipoidica, a disease of changing concepts. AMA Arch Dermatol 1956;74:280-5.

10.  Muller SA, Winkelmann RK. Necrobiosis lipoidica diabeticorum. A clinical and pathological investigation of 171 cases. Arch Dermatol 1966;93:272-81.

11.  Shall L, Mullard LG, Stevens A, Tattersall RB, Peacock I. Necrobiosis lipoidica: ‘the footprint not the footstep’. Br J Dermatol 1990;123(s37):47.

12.  Dandona P, Freedman D, Barter S, Majewski BB, Rhodes EL, Watson B. Glycosylated haemoglobin in patients with necrobiosis lipoidica and granuloma annulare. Clin Exp Dermatol 1981;6:299-302.

13.  Lowitt MH, Dover JS. Necrobiosis Lipoidica. J Am Acad Dermatol 1991;25(5 Pt 1):735-48.

14.  Timshina DK, Thappa DM, Agrawal A. A clinical study of dermatoses in diabetes to establish its markers. Indian J Dermatol 2012;57:20-5.

15.  Ragunatha S, Anitha B, Inamadar AC, Palit A, Devarmani SS. Cutaneous disorders in 500 diabetic patients attending diabetic clinic. Indian J Dermatol 2011;56:160-4.

16.  Ahmed K, Muhammad Z, Qayum I. Prevalence of cutaneous manifestations of diabetes mellitus. J Ayub Med Coll Abbottabad 2009;21:76-9.

17.  Shahzad M, Al Robaee A, Al Shobaili HA, et al. Skin manifestations in diabetic patients attending a diabetic clinic in the Qassim region, Saudi Arabia. Med Princ Pract 2011;20:137-41.

18.  Cohen O, Yaniv R, Karasik A, Trau H. Necrobiosis lipoidica and diabetic control revisited. Med Hypotheses 1996;46:348-50.

19.  Patel GK, Harding KG, Mills CM. Severe disabling Köebnerizing ulcerated necrobiosis lipoidica successfully managed with topical PUVA. Br J Dermatol 2000;143:668-9.

20.  Lim C, Tschuchnigg M, Lim J. Squamous cell carcinoma arising in an area of long-standing necrobiosis lipoidica. J Cutan Pathol 2006;33:581-3.

21.  Gudi VS, Campbell S, Gould DJ, Marshall R. Squamous cell carcinoma in an area of necrobiosis lipoidica diabeticorum: a case report. Clin Exp Dermatol 2000;25:597-9.

22.  Muller SA, Winkelmann RK. Necrobiosis lipoidica diabeticorum histopathologic study of 98 cases. Arch Dermatol 1966;94:1-10.

23.  Suárez-Amor O, Pérez-Bustillo A, Ruiz-González I, Rodríguez-Prieto MA. Necrobiosis lipoidica therapy with biologicals: an ulcerated case responding to etanercept and a review of the literature. Dermatology 2010;221:117-21.

24.  O'Reilly K, Chu J, Meehan S, Heller P, Ashinoff R, Gruson L. Necrobiosis lipoidica. Dermatol Online J 2011;17:18.

25.  Tan E, Patel V, Berth-Jones J. Systemic corticosteroids for the outpatient treatment of necrobiosis lipoidica in a diabetic patient. J Dermatolog Treat 2007;18:246-8.

26.  Batchelor JM, Todd PM. Treatment of ulcerated necrobiosis lipoidica with intravenous immunoglobulin and methylprednisolone. J Drugs Dermatol 2012;11:256-9.

27.  Binamer Y, Sowerby L, El-Helou T. Treatment of ulcerative necrobiosis lipoidica with topical calcineurin inhibitor: case report and literature review. J Cutan Med Surg 2012;16:458-61.

28.  Conte H, Milpied B, Kaloga M, et al. Treatment of pre-ulcerative necrobiosis lipoidica with infliximab. Acta Derm Venereol 2011;91:587-8.

29.  Boyd AS. Treatment of necrobiosis lipoidica with pioglitazone. J Am Acad Dermatol 2007;57(5 Suppl):S120-1.

30.  Schofield C, Sladden MJ. Ulcerative necrobiosis lipoidica responsive to colchicine. Australas J Dermatol 2012;53:e54-7.

31.  Eberle FC, Ghoreschi K, Hertl M. Fumaric acid esters in severe ulcerative necrobiosis lipoidica: a case report and evaluation of current therapies. Acta Derm Venereol 2010;90:104-6.

32.  Berking C, Hegyi J, Arenberger P, Ruzicka T, Jemec GB. Photodynamic therapy of necrobiosis lipoidica--a multicenter study of 18 patients. Dermatology 2009;218:136-9.


  • There are currently no refbacks.

The Journal of the Association of British Clinical Diabetologists