PRACTICE DEVELOPMENT

Understanding lipoidica diabeticorum

KEY WORDS diabeticorum (NLD) is an uncommon inflammatory condition  Mellitus that usually affects people with diabetes mellitus (DM), in which shiny, red-brown or   annulare yellowish patches develop in the skin often on the lower limbs. The course of the Necrobiosis lipoidica is unpredictable with recurrence and flare-ups common occurrences. In her article, diabeticorum Wounds Trudie Young gives an overview of this condition, its aetiology, clinical presentation, complications and treatment options

iabetes mellitus (DM) is a heterogenous described by Urbach in 1932 and subsequently group of metabolic disorders characterised by Oppenheim in 1932 when he referred to by elevated serum glucose levels resulting NLD as ‘dermatitis atrophicans diabetica’ Din defects in insulin production in the beta cells of (Drury et al, 1967; Hammer et al, 2016). A year the islets of Langerhans in the pancreas. In type 1 after Oppenheim’s presentation at the Vienna DM the destruction/inactivity of insulin-producing Dermatological Society, Klaber presented a patient beta cells results in dependence on exogenous with NLD to the Royal Society of Medicine, UK, insulin. Whereas type 2 non-insulin dependent (Klaber, 1933; McGuinness and Padhiar, 1997). DM can be controlled by a combination of oral Subsequently Gordon published the histology medication and diet. Type 2 DM is associated with report of a patient with NLD in the Journal of the older age, obesity, physical inactivity and family Royal Society of Medicine (Gordon, 1937). history of the disease (Chakrabarty et al, 2002). Necrobiosis literally means a state of life The number of adults living with DM and death and is therefore self-cancelling, worldwide in 2017 was 425 million and this necro meaning degeneration and bio meaning is expected to rise to 629 million by 2045 regeneration. Lipoidica refers to the accumulation (International Diabetes Federation, 2018) (Figure of fat which is not a primary event of the disease, 1). There is an increase in DM in the younger diabeticorum links it to DM (McGuinness and population due to sedentary lifestyles and diet Padhiar, 1997). (Karadag et al, 2018). NLD is a rare non-infectious granulomatous The complications of DM are as a result of disorder of the skin which occurs in 0.3% of people metabolic, hormonal, environmental and genetic with both type 1 and type 2 DM (Du Vivier, 2002; factors which can affect all organs of the body Mistry et al, 2017). It is more common in the including the skin (Karadag et al, 2018). The female population with the average age of onset complications include retinopathy, neuropathy being 30-years old. It can be found in people and nephropathy. DM has been implicated as the without DM although this may be a precursor single largest cause of end-stage renal disease, the to the disease and the individual will require main reason for non-traumatic amputation and an regular monitoring for the development of DM. independent risk factor for cardiovascular disease Sanotos et al (2013) present one of many case TRUDIE YOUNG (Chakrabarty et al, 2002). One-third of individuals studies in the literature of an individual with Director of Education and Train- with DM will have some form of disease-related typical NLD on the pretibial area that did not ing and Tissue Viability Nurse, Welsh Wound Innovation Centre, dermatological problem (Stewart, 2006). have DM and it was thought to be preceding the Llantrisant, Wales, UK Necrobiosis lipoidica diabeticorum (NLD) was onset of DM. The first incidence of NLD reported

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Figure 1. The International IDF DIABETES ATLAS Diabetes Federation (IDF) Atlas 8th edition 2017 (with kind permission from the

NORTH AMERICA & CARIBBEAN EUROPE IDF, 2017) Half the global diabetes healthcare spending 1 in 7 adults in this region is at risk USD 1 in every USD 4 of the global diabetes 1 in 6 live births is affected by occurs in this region of type 2 diabetes healthcare spending occurs in this region hyperglycaemia in pregnancy

2045 62million +35% 2045 46million 67million 2017 +16% 58million 2017

2045 WESTERN 82million +110% PACIFIC million 39 1 in 3 adults with 2017 diabetes lives in this region MIDDLE EAST 1 in 3 deaths AND NORTH AFRICA attributable to 1 in 5 live births are diabetes happen affected by hyperglycaemia in this region in pregnancy 1 out of 2 deaths due to 2045 2045 diabetes were in people 183million 42million +62% under the age of 60 +15% 159million 26million 2017 2017

SOUTH AND CENTRAL AMERICA

2 out of 5 people with 2045 2045 diabetes were undiagnosed 41million 151million Only 4% of global healthcare +156% +84% expenditure for diabetes 16million 82million spent in this region 2017 2017

AFRICA 2045 SOUTH-EAST ASIA 2 out of 3 people with 629million WORLD diabetes are undiagnosed 1 in 5 adults with diabetes lives in this region 425million +48% 3 out of 4 deaths due to diabetes were in people under 1 in 4 live births is affected 2017 the age of 60 by hyperglycaemia in pregnancy

Almost half of the 4 million people who die 4 out of 5 people with diabetes live in Among high income countries, 79% of global healthcare from diabetes are under the age of 60 low- and middle-income countries expenditure on diabetes was spent, but only 36% of deaths below 60 years occured ColourDeaths attributable palette // to Regionsdiabetes by age (20-79 years) Colour palettePrevalence // 6 (%) colour estimates way of diabetes (20-793 colour years) way // TablesTotal in healthcareAppendices expenditure and meanBrand healthcare Colours expenditure per person and per income group by income group and age 7,000 6,767 600 80% 4,5 575 25% 73% 6,000 500 70% 4 22% in the non-diabetic population was described membrane.21% This does not lead to a decrease in 20% 60% 3,5 20% 19% 5,000 400 3.2 High income countries 17% Middle income countries 19% 19% 50% 3 18% 18% Low income countries 14% 4,000 46% 15% by Goldsmith in 1935 (Kota et al, 2012). the diameter of the capillary lumen, however,300 40% 2,5 12% 15% 36% 3,000 12% 30% 1,5 10% 9% 200 6% 2,000 There is debate in the literature regarding the the structural alterations152 adversely affect 5% 9% 20% 1 8% 8% 5% 4% 7% 7% 7% 100 6% 6% 1,000 0.5 0,5 10% 2% 5% 5% 468 0.2 1% 4% relationship of NLD to diabetes with3% Hammer the vasodilation capacity, cellular70 1 adhesion, (Billion USD) expenditure healthcare Total 0 0 Mean healthcare expenditure per person (USD) per person expenditure Mean healthcare Proportion of deaths before 60 years of deaths before Proportion 0% 0 in millions diabetes Deaths due to 0% High income countries Middle income countries Low income countries 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 High income countries Middle income countries Low income countries et al (2016) establishing a link between type proliferation, differentiation and gene expression Half of people with diabetes 352 million people are at risk The top 10 countries for number of adults with diabetes don’t know they have it of developing type 2 diabetes account for 60% of people with diabetes and 69% of global 1 DM and NLD in a retrospective review of (Tecilazichhealthcare et al, expenditure 2011). on diabetes Undiagnosed percentage and undiagnosed cases of Number of adults (20-79 years) with IGT per IDF region, 2017 Top 10 countries for number of adults with diabetes (20-79 years) and their healthcare 64,133diabetes (20-79patients. years) by region In addition, there are multiple Immunofluorescenceexpenditure, 2017 348 studies have 127 120 120 million people 114 billion ID

110 case100% reports highlighting NLD100 alongside poor demonstrated108 the presence of immunoglobulin,108 millions 120 millon 90% 90 96 96 glycaemic control (Yigit 85and Estrada, 2002; fibrinogen and complement deposition 80% 80 100 Bonura et al, 2014). However, following a on the 84vascular wall of the capillaries84 and 70% 69% 70 73 72 72 80 60% 60 review of the literature57% Mistry et al (2017) state occasionally along the dermal/epidermal 54% 60 60 50% 49% 47 50 60 54 that there is currently insufficient evidence to junction 48which may indicate an immunological-42 48 40% 40% 40 38% 38% 40 36 40 32 30 36 support30% or refute the claim 30 of a link36 between33 33 mediated29 vascular disease mechanism in NLD 24 24 24 20% 22 19 20 19 20 glycaemic control17 and the manifestation of (Scaramuzza et al, 2012). 20 13 12 10 10% 10 10 10 12 12 5 9 8 7 8 8 2 NLD.0 Consequently, the disease0 is sometimes The dermal degenerates producing 0 0 0 AFR EUR MENA NAC SACA SEA WP AFR EUR MENA NAC SACA SEA WP China India United Brazil Mexico Indonesia Russian Egypt Germany Pakistan referred to as necrobiosis lipoidica (NL) with the dermal inflammationStates at the Federationsite of the lesion. Corporate sponsors Need more information? 'diabeticorum'IDF would like to express its thanks being to the following dropped from the title. Microangiopathic vesselCheck changes www.diabetesatlas.org can contribute supporters of the IDF Diabetes Atlas 8th edition: or scan QR code to the development of collagen degradation AETIOLOGY and subsequent dermal inflammation (Mazur The aetiology of the disease is said to have three et al, 2011). mechanisms; microangiopathic ischaemia, There is debate regarding which component an immunological component and collagen is the leading underlying mechanism, e.g. abnormalities (Bonura et al, 2014). Doppler studies have demonstrated that an Structural changes in diabetic microcirculation underlying inflammatory process, rather than results in a thickening of the basement microangiopathic ischaemia of the skin plays the

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most important role in the pathogenesis of NLD. COMPLICATIONS Whereas glycoprotein deposition on the vascular The three main complications reported in NLD wall of skin capillaries due to the underlying are the development of malignancy within the diabetes results in the lower oxygen tension within lesion, secondary infection in the wound bed and the lesion (Basoulis et al, 2015). There is a school the unsightly scarring which produces a cosmetic of thought that views NLD as a primary disease disability (Guidi et al, 2000; McGuinness and of collagen with inflammation occurring as a Padhiar, 1997). secondary event (Mazur et al, 2011). Histological examination of the lesions DIFFERENTIAL DIAGNOSIS demonstrates the presence of interstitial and is a chronic asymptomatic palisaded in a layered presentation that dermatosis found on dorsum of the hands, feet involve the subcutaneous tissue and the and elbow and it can be difficult to distinguish (Korber and Dissemond, 2007; Kota et al, 2012). from NLD. It is characterised by collagen Dermal collagen degeneration is seen along with an degeneration and reactive inflammation and Figure 2. NLD in pre-tibial area atrophic and a thickening of blood vessel fibrosis (Chakrabarty et al, 2002; Karadag et al, with early onset plaque present walls (Kota et al, 2012; Lima et al, 2017). 2018). In addition, patients with sarcoidosis can have similarly presenting lesions to those in NLD CLINICAL PRESENTATION (Mistry et al, 2017). The disease starts with red that slowly enlarge into erythematous non-scaling plaques TREATMENT (Figure 2) with waxy indurated yellow-brownish There are no recognized standard treatment telangiectatic centres and raised edges (Phillips, plans for NLD. The evidence currently available 2003; Tecilazich et al, 2011; Motolese et al, 2015). is insufficient to give definitive recommendations The plaques can precede ulcerations by months as regards the systemic treatment of NLD or years (Dissemond et al, 2018). It is particularly (Dissemond et al, 2018). prevalent on the lower limbs; however, it can An early theory regarding the aetiology of NLD present on the fingers, dorsum of hands, face, based on experiences within the Mayo clinic scalp, abdomen, interscapular region and penis in USA was that the causative factor was local (Drury et al, 1967; Kanchan et al, 2001; Du Vivier, lipid disturbance in the skin based on a general 2002; Korber and Dissemond, 2007; Scaramuzza et disturbance in fat metabolism. Therefore, the al, 2012; Bonura et al, 2014; Mistry et al, 2017). The suggested treatment was to put the patient on presentation on the lower limbs is often bilateral a low-fat diet, however, with hindsight it is not Figure 3. Active NLD lesion and symmetrical and may present with single or surprising that this did not result in an increase in multiple lesions (Tecilazich et al, 2011). healing rates (Hildebrand et al, 1940). The lesions are usually asymptomatic and are Systemic, intralesional and topical application not associated with any serious complications of corticosteroids appear to be the mainstay of (Stewart, 2006). However, pruritis and pain have treatment for NLD (Guidi et al, 2000). Success been recorded at the site of the lesions in patients has been reported using triamcinolone (an with NLD (Drury et al, 1967; Dissemond et al, intralesional steroid) applied to modulate the 2012). The disease process has periods of activity inflammation in the active borders of enlarging when the lesions commence and enlarge (Figure 3) lesions (Lima et al, 2017). Non-steroidal anti- and periods of inactivity when the lesions become inflammatory agents have also been used to atrophied (Stewart, 2006). NLD is self-limiting and modify the inflammatory component of the can resolve spontaneously, however, recurrence is disease. a probability and flare ups are frequent (Wake and The use of immune modulating agents such as Fang, 2006; Mistry et al, 2017). Infliximab given intravenously or intralesional can There are reports in the literature of NL and NLD lead to a reduction of pro-inflammatory cytokines occurring following tattooing and removal levels. Infliximab is a monoclonal antibody (Babin-Muise et al, 2012; Jibreal et al, 2017). antagonist to tumor factor α (Kota et al,

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2012). Basoulis et al (2015) presented a single case involved in wound healing (Kota et al, 2002; Keller, study in which the NLD healed after four monthly 2018). sessions of systemic Infliximab. Nevertheless, Medication used to influence the blood flow treatment with immune modulating agents has in NLD include aspirin which is a cutaneous the potential for serious infections to develop blood flow enhancer and pentoxifylline which e.g. reactivation of latent tuberculosis, invasive inhibits platelet aggregation and decreases blood fungal infections and infections by opportunistic viscosity (Kota et al, 2012). Templeton and pathogens, they also have an association with Caughman (1993) report success in using asprin malignancies (Basoulis et al, 2015). Tacrolimus, a and pentoxifylline along with whirlpool therapy, calcineurin inhibitor, and Cylosporin A have been topical corticosteroids and occlusive dressings. used in NLD to inhibit interlukin-2 production by Conversely, these treatments were reported as T-helper cells preventing T-cell proliferation and being unsuccessful in a single individual who thereby suppressing the immune response (Korber was subjected to recurrent infections along with and Dissemond, 2007; Kota et al, 2012). Tacrolimus NLD. They subsequently responded to a regimen has produced a positive response when used in including long term flucloxacillin, topical hydrogel, the early inflammatory phase of the disease by conservative sharp debridement and 3 layers of influencing T-cell activation (Stewart, 2006). tubigrip to provide modified compression therapy. A retrospective case series of patients with The individual had been non-healing for 18 ulcerated non-healing NLD who were receiving months, however, after the introduction of the new standard wound care, plus weekly applications regimen healed after 28 weeks (Nash et al, 1994). of bioengineered neonatal human dermal tissue Conservative sharp debridement and compression was presented by Rader and Wilson (2013). The was employed successfully in another case, this metabolically active cells in the human tissue time with the addition of a protease modulating provide collagen I and III, fibronectin, tenascins dressing (Stewart, 2006). and glycosaminoglycans and growth factors, which A variety of other treatments have been may help to alleviate the collagen degradation recommended for the treatment of NLD; laser at the dermal and subcutaneous tissues in NLD. therapy, surgery and grafting, psoralen and Additionally, the living cells in the human dermal ultraviolet A radiation (PUVA), (Chakrabaty et al, tissue promote cell proliferation and angiogenesis. 2002; Stewart, 2006; Mazur et al, 2011; Kota et al, During the case review no secondary infections 2012). or adverse events were noted. Previous treatment The proponents of collagen degeneration as included moist wound healing and topical steroids. the main aetiology of NLD recommend avoiding The duration to healing improved from 40 weeks trauma to prevent the onset of the disease to 7 weeks when treated with the human dermal (Scaramuzza et al, 2012; Mitre and Wang, 2016). tissue (Radar and Wilson, 2013). Whereas blood sugar control may help to reverse Another treatment evaluated in a small group hyper-glycaemia-induced microangiopathy of patients (15) with recalcitrant NLD was (Basoulis et al, 2015). Numerous case reports homologous platet-rich plasma (prp), which is a exist when tight glucose control was part of the concentration of human platelets in a small volume treatment regimen, nevertheless this remains of plasma, it is proposed that the treatment will a contentious issue (Yigit and Estrada, 2002; degranulate the α-granules in platelets and release Scaramuzza et al, 2012; Bonura et al, 2014; Mitre the growth factors stored within the α-granules. and Wang, 2016). All patients showed a marked enhancement in wound healing with a mean reduction in lesion CONCLUSION size of 79% and no adverse effects were noted Kota et al (2012) refers to NLD as the benign devil (Motolese et al, 2015). Topical becaplermin is a gel which accompanies diabetes. This disease is also containing human-derived growth factor that has found in non-diabetics and referred to as NL. been used to treat NLD, presumably by promoting The disease is said to have three elements; chemotaxis and the proliferation of the cells vascular, immune-mediated and collagen

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components with debate existing around the International Diabetes Federation (2017) IDF Diabetes Atlas, 8th edn. Brussels, Belgium. http://www.diabetesatlas.org influence of each aspect. Jibreal HA, Manoharan H, Weedon D (2017) Necrobiosis lipoidica The early changes are papules that develop following qswitched laser tattoo removal. Australas J Dermatol 58(4): into plaques which then may remain static or 268-e27 eventually develop into intractable non-healing Kachan P, Janth D, Shenoi S, Sandra A (2001) Necrobiosis lipoidica diabeticorum. Indian Journal of 46(4): 231–33 asymptomatic lesions with a predilection for the Karadag AS, Ozlu E, Lavery MJ (2018) Cutaneous manifestations of female population and the pretibial area. The diabetes mellitus and the metabolic syndrome. Clin Dermatol Rep 36(1): disease is diagnosed by histological findings from 89 –93 Keller JJ (2018) Leg ulcers: Expanding the differential. Curr Dermat Rep 7(3): a biopsy of the lesion. 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