Necrobiosis Lipoidica 

Updated: Feb 12, 2018
Author: Cheryl J Barnes, MD; Chief Editor: George T Griffing, MD 

Overview

Background

Necrobiosis lipoidica is a disorder of collagen degeneration with a granulomatous response, thickening of blood vessel walls, and fat deposition. The main complication of the disease is ulceration, usually occurring after trauma. Infections can occur but are uncommon. There have been rare reported cases of squamous cell carcinomas developing in chronic lesions of necrobiosis lipoidica.[1, 2, 3]

The condition was first described in 1929, by Oppehhein, who called it dermatitis atrophicans lipoidica diabetica; in 1932, however, the disease was renamed necrobiosis lipoidica diabeticorum (NLD), by Urbach.

In 1935, Goldsmith reported the first case in a nondiabetic patient. Other cases of necrobiosis lipoidica diabeticorum in nondiabetic patients were described by Meischer and Leder, in 1948. Rollins and Winkelmann, in 1960, also described this condition in nondiabetic patients, and a renaming of the disorder was suggested to exclude diabetes from the title.[4] Today, the term necrobiosis lipoidica is used to encompass all patients with the same clinical lesions, regardless of whether or not diabetes is present.

Etiology

Despite extensive studies, the etiology of necrobiosis lipoidica is still uncertain. Because of the strong relationship between diabetes and necrobiosis lipoidica diabeticorum, many studies have focused on diabetic microangiopathy as the leading etiologic theory. Diabetic alterations of the kidney and eye vasculature are similar to the vascular changes seen in necrobiosis lipoidica. A deposition of glycoprotein in blood vessel walls may be the cause of diabetic microangiopathy. A similar glycoprotein deposition is seen in necrobiosis lipoidica.

Another theory is based on the deposition of immunoglobulins, the third component of complement and fibrinogen in the blood vessel walls of patients with necrobiosis lipoidica. Some believe that an antibody-mediated vasculitis may initiate the blood vessel changes and subsequent necrobiosis in necrobiosis lipoidica.

An additional etiologic theory focuses on the abnormal collagen in necrobiosis lipoidica. It is well established that abnormal and defective collagen fibrils have been responsible for diabetic end-organ damage and accelerated aging. Lysyl oxidase levels have been found in some diabetic persons to be elevated and are responsible for increased collagen cross-linking. Increased collagen cross-linking could explain basement membrane thickening in necrobiosis lipoidica.

Other theories link trauma and inflammatory and metabolic changes as a possible etiology. It also has been found that there may be impaired neutrophil migration leading to an increased number of macrophages, possibly explaining the granuloma formation in necrobiosis lipoidica. The pathogenesis of necrobiosis lipoidica has not been demonstrated to be linked to genetic factors.

Tumor necrosis factor (TNF)–alpha has a potentially critical role in conditions such as disseminated granuloma annulare and necrobiosis lipoidica. It is found in high concentrations in the sera and skin in patients with these conditions.

A study by Hammer et al of 64,133 patients with type 1 diabetes found that those with necrobiosis lipoidica tended to have worse metabolic control, a longer duration of diabetes, and a need for higher insulin doses than did the other patients. In addition, a correlation was found between necrobiosis lipoidica and celiac disease, and a greater percentage of patients with necrobiosis lipoidica had elevated thyroid antibodies.[5]

A retrospective study by Erfurt-Berge et al of 100 patients with necrobiosis lipoidica found female sex and middle age to be characteristic of patients with the disease. The investigators also reported that ulceration, seen in 33% of cases, was most prevalent in males and in patients with diabetes mellitus and that thyroid dysfunction occurred in 15% of all cases.[6]

A study by Jockenhöfer et al found that among 262 patients with necrobiosis lipoidica, comorbidities other than diabetes mellitus (34.4% of patients) included essential hypertension (9.2% of patients), obesity (4.6% of patients), chronic heart failure (4.1% of patients), and dyslipidemias (2.3% of patients).[7]

Epidemiology

The average age of onset for necrobiosis lipoidica is 30 years, but it can occur at any age. The age of onset ranges from infancy to the eighth decade. The disease tends to develop at an earlier age in patients with diabetes. It also shows a sex predilection, being 3 times more common in women than in men.

Occurrence in the United States

Necrobiosis lipoidica has been described in about 0.3% of diabetic patients. In one study, necrobiosis lipoidica was shown to precede the onset of diabetes mellitus in 15% of patients. In addition, 60% of patients had the diagnosis of diabetes mellitus prior to the onset of necrobiosis lipoidica, while 25% of patients had lesions that appeared with the onset of diabetes mellitus. The presence or progression of necrobiosis lipoidica does not correlate with how well diabetes is controlled.

Prognosis

Treatment for necrobiosis lipoidica is not very satisfactory. The disease is typically chronic with variable progression and scarring. Squamous cell cancers have been reported in older lesions of necrobiosis lipoidica related to previous trauma and ulceration.[1]

From a cosmetic standpoint, the prognosis of necrobiosis lipoidica is poor. Treatment is helpful in halting the expansion of individual lesions, which tend to run a chronic course. Lesional ulcerations can cause significant morbidity, requiring prolonged wound care. These ulcerations can be painful, become infected, and heal with scarring.

 

Presentation

History and Physical Examination

History

Patients usually present with shiny, asymptomatic patches that slowly enlarge over months to years. The patches are initially red-brown and progress to yellow, depressed, atrophic plaques. Ulcerations can occur, typically after trauma and occasionally with associated pain. The patient's main complaint is the unsightly cosmetic appearance of the lesions.

Physical examination

Skin lesions of classic necrobiosis lipoidica begin as 1- to 3-mm, well-circumscribed papules that expand to form plaques with active, more-indurated borders and waxy, strophic centers. Initially, these plaques are reddish brown but progressively become more yellow, shiny, and atrophic in appearance. (See the images below.)

Typical presentation of necrobiosis lipoidica on t Typical presentation of necrobiosis lipoidica on the lower pretibial legs.
Red-brown plaque with yellow atrophic center on lo Red-brown plaque with yellow atrophic center on lower leg.

Most cases of necrobiosis lipoidica occur on the pretibial area, but cases have been reported on the face, scalp, trunk, and upper extremities, where the diagnosis is more likely to be missed. Multiple telangiectatic vessels can be seen on the surface of the thinning epidermis.

Ulceration at the site of trauma and subsequent infection are occasional complications of necrobiosis lipoidica. The Koebner phenomenon has been well established in patients with necrobiosis lipoidica, especially in patients with vasculitis at the site of trauma.[8]

Miller reported a case of a woman with known type 1 diabetes mellitus who developed biopsy-proven necrobiosis lipoidica in a cholecystectomy scar and also on her abdomen at insulin injection sites.

In most patients, the lesions of necrobiosis lipoidica are multiple and bilateral. The lesions may become painless because of cutaneous nerve damage (75% of cases), or they may be extremely painful (25% of cases).

 

DDx

Diagnostic Considerations

The clinical appearance of necrobiosis lipoidica is distinctive, yet there are many atypical presentations, and early forms can be hard to recognize.[9] Note the following:

  • Superficial annular lesions can resemble granuloma annulare

  • Yellow annular lesions of necrobiosis lipoidica with a fatty infiltration can resemble xanthomas

  • Necrobiotic xanthogranuloma is a rare disease that can mimic necrobiosis lipoidica clinically and histologically; necrobiotic xanthogranuloma has been associated with paraproteinemia and some hematologic malignancies, which is not the case with necrobiosis lipoidica

  • The clinical and histologic appearance of sarcoidosis of the skin can be like that of necrobiosis lipoidica

  • Rheumatoid nodules also have a histologic appearance similar to that of necrobiosis lipoidica, but clinically they appear as subcutaneous nodules rather than as atrophic plaques

  • Ulcerated necrobiotic lesions also have been described in patients with rheumatoid arthritis

Differential Diagnoses

 

Workup

Approach Considerations

Laboratory findings are not helpful in the diagnosis of necrobiosis lipoidica. When necrobiosis lipoidica is diagnosed, some advocate checking for glucose intolerance to evaluate for the presence or absence of diabetes mellitus. Necrobiosis lipoidica has been the first sign of diabetes in some patients and a clue to possible diabetic potential in others.

Histologic Findings

Histopathologically, necrobiosis lipoidica presents with interstitial and palisaded granulomas that involve the subcutaneous tissue and dermis. At low magnification, lesions of necrobiosis lipoidica have a very characteristic appearance. The granulomas are arranged in a tierlike (layered) fashion and are admixed with areas of collagen degeneration. The granulomas are composed of histiocytes (some of them multinucleated), lymphocytes, occasional plasma cells, and eosinophils. Reduction in the number of intradermal nerves is an additional feature of necrobiosis lipoidica.

The main findings on histopathology are thickening of the blood vessel walls and endothelial cell swelling found in the middle to deep dermis, characteristics shared with diabetic microangiopathy.

Direct immunofluorescence microscopy of necrobiosis lipoidica has demonstrated immunoglobulin M (IgM), IgA, C3, and fibrinogen in the blood vessels, which cause the vascular thickening.[10] In nondiabetic patients with necrobiosis lipoidica, the vascular changes are not as prominent.

A study by Ramadan et al indicated that dermoscopy can aid in differentiating cutaneous sarcoidosis from necrobiotic granulomas, even in patients who have undergone treatment with systemic steroids. The investigators found that although some dermoscopic features overlap between these conditions, cutaneous sarcoidosis differs dermoscopically from necrobiotic granulomas by its association with a pink homogenous background, translucent orange regions, white scarlike depigmentation, and fine white scales. Moreover, a significant association was found between necrobiotic granulomas and a mixed pink, white, and yellowish background. In addition, features distinguished in patients treated with systemic steroids did not significantly vary from those found in untreated patients.[11]

 

Treatment

Approach Considerations

Treatment for necrobiosis lipoidica is not very effective, partially because the exact etiology remains unknown. Because localized trauma can cause necrobiosis lipoidica to ulcerate, protection of the legs with elastic support stockings and leg rest may be helpful.

Topical and intralesional corticosteroids can lessen the inflammation of early active lesions and the active borders of enlarging lesions but have little beneficial effect on so-called “burned out” atrophic lesions. In fact, with atrophic lesions, corticosteroid use may cause further atrophy.

In 2005, Clayton and Harrison reported a case of ulcerated necrobiosis lipoidica that was treated successfully with 0.1% topical tacrolimus ointment applied twice daily for 1 month.[12] Tacrolimus is a calcineurin inhibitor that has been shown to have a mechanism of action similar to that of cyclosporine in that it prevents T-cell activation. Cyclosporine at doses of 2.5 mg/kg/day has also been used with success in treating ulcerated necrobiosis lipoidica.[13]

A study by Ginocchio et al also indicated that topical tacrolimus is effective, as demonstrated in the case of a nondiabetic woman aged 55 years with refractory ulcerated necrobiosis lipoidica. In the report, the ulcerations improved significantly after treatment, a 10-month therapy involving daily application of 0.1% tacrolimus ointment and multilayer compression wraps.[14]

Spencei and Nahass described a case of ulcerated necrobiosis lipoidica that was treated successfully with topically applied bovine collagen.[15] Collagen is believed to improve granulation tissue by supporting fibroblast activity and by promoting wound debridement by increasing the number of macrophages and neutrophils at the wound site.

De Rie et al reported successful treatment of necrobiosis lipoidica with topical psoralen plus ultraviolet-A (UVA) light therapy.[16] Thirty patients were treated with twice-weekly courses of topical psoralen plus UVA light therapy. Five patients had complete clearing of their ulceration and erythema, and 11 patients showed significant improvement in their disease. UVA-1 and photodynamic therapy have been reported to be as successful.[17, 18]

Ticlopidine,[19] nicotinamide,[20] clofazimine,[21, 22] and perilesional heparin injections[23] have been used in uncontrolled studies and appeared to benefit some patients with necrobiosis lipoidica.

According to W.R. Heymann, tretinoin has been used to diminish the atrophy associated with necrobiosis lipoidica (personal communication).[24]

Durupt et al reported successful treatment of necrobiosis lipoidica with chloroquine and hydroxychloroquine. Improvement was seen within 3- 6 months of treatment.[25]

Surgical and laser therapy

Excision and grafting have been successful, but recurrence may take place secondary to the underlying vascular damage. Poor healing of the graft site is not uncommon.[26]

Laser care is also described. Moreno-Arias and Camps-Fresneda treated necrobiosis lipoidica with a pulse dye laser (Candela SPTL; Irvine, Mass).[27] They reported overall cosmetic improvement after 3 treatment sessions with respect to erythema and telangiectasis. Stabilization of the lesions was also achieved with the laser treatments.

Antiplatelet Aggregation Therapy

Antiplatelet aggregation therapy with aspirin and dipyridamole has been tried owing to a belief that necrobiosis lipoidica results from platelet-mediated vascular occlusion or immune mechanisms that alter platelet survival.[28] These drugs are thought to prolong platelet survival time and, hence, prevent further worsening of necrobiosis lipoidica. The results of double-blind studies with aspirin and dipyridamole have varied but overall have shown some beneficial effects from the therapy.

Littler and Tschen reported a case of necrobiosis lipoidica that was treated successfully with pentoxifylline, a drug used in the treatment of intermittent claudication.[29] Pentoxifylline not only inhibits platelet aggregation but is also believed to decrease blood viscosity by increasing fibrinolysis and red blood cell deformity.

Inhibition of Tumor Necrosis Factor

As previously mentioned, TNF-alpha may have a critical role in conditions such as disseminated granuloma annulare and necrobiosis lipoidica. It occurs in high concentrations in the sera and skin in patients with these conditions.

Boyd reported that the thiazolidinedione drug class has been used with some success in necrobiosis lipoidica. These drugs function as potent agonists for the peroxisome proliferator–activated receptor-gamma (PPARgamma). These receptors have been found in adipose tissue and function as important mediators in lipid storage and adipocyte differentiation.[30] PPARgamma activation diminishes TNF-alpha production and inhibits the action of proinflammatory cytokines, which may help healing in necrobiosis lipoidica.[31, 32]

In several case reports, the TNF-alpha inhibitors etanercept, adalimumab, and infliximab were shown to improve chronic granulomatous skin disorders.[33, 34] Infliximab is a chimeric monoclonal antibody that acts to inhibit TNF-alpha. Kolde et al reported infliximab as a successful treatment option for ulcerated necrobiosis lipoidica.[35] Successful treatment of necrobiosis lipoidica with thalidomide, another drug with anti-TNF effects, has also been reported.[36]

 

Medication

Medication Summary

Double-blind studies of the treatment of necrobiosis lipoidica with aspirin and dipyridamole have had varied results but overall have shown some beneficial effects from the therapy. The treatment is based on a theory that necrobiosis lipoidica results from platelet-mediated vascular occlusion or immune mechanisms that alter platelet survival.[28] These drugs are thought to prolong platelet survival time and, hence, prevent further worsening of necrobiosis lipoidica.

Littler and Tschen described the successful use of pentoxifylline to treat a case of necrobiosis lipoidica.[29] Pentoxifylline inhibits platelet aggregation and is believed to decrease blood viscosity by increasing fibrinolysis and red blood cell deformity.

Uncontrolled studies have suggested that ticlopidine,[19] nicotinamide,[20] clofazimine,[21, 22] and perilesional heparin injections[23] can benefit some patients with necrobiosis lipoidica.

Hemorheologic Agents

Class Summary

These agents reduce complications resulting from increased blood viscosity.

Pentoxifylline (Trental)

Pentoxifylline may alter the rheology of red blood cells, consequently reducing blood viscosity. It increases fibrinolysis and red blood cell deformity and also inhibits platelet aggregation.

Antiplatelet Agents

Class Summary

These drugs inhibit platelet aggregation. The drugs are thought to prolong platelet survival time and, hence, prevent further worsening of necrobiosis lipoidica. They also help prevent cerebrovascular accidents and improve renal and systemic function.

Ticlopidine

Ticlopidine is a second-line antiplatelet therapy for patients who fail aspirin therapy.

B Vitamins

Class Summary

These agents may inhibit the synthesis of low-density lipoprotein and very-low-density lipoprotein. This inhibition results in a decrease of total plasma cholesterol. Nicotinamide, and not niacin or other niacin preparations, is a treatment option.[20] Nicotinamide is the physiologically active form of niacin, vitamin B-3. Unlike niacin, nicotinamide in high doses does not lower lipid levels or cause flushing. However, it does exert significant anti-inflammatory effects.

NADH (Nicotinamide adenine dinucleotide)

Nicotinamide moderates inflammatory reactions by inhibiting leukocytic chemotaxis and leukocytic release of lysosomal enzymes. It has been shown to inhibit lymphocytic transformation, antibody production, and mast cell degranulation.

Immunomodulators

Class Summary

Immunomodulators inhibit key factors responsible for the inflammatory response to tissue insult.

Clofazimine (Lamprene)

Clofazimine is known to have anti-inflammatory properties in controlling erythema nodosum leprosum reactions, but its mechanism of action is unknown.

Anticoagulants, Hematologic

Class Summary

Anticoagulants inhibit the formation of blood clots resulting from blood disorders.

Heparin

Heparin augments the activity of antithrombin III and prevents the conversion of fibrinogen to fibrin. It does not actively lyse, but it can inhibit further thrombogenesis. Heparin prevents the reaccumulation of clots after spontaneous fibrinolysis.

Retinoid-like Agents, Topical

Class Summary

Retinoids regulate cell growth and differentiation.

Tretinoin topical (Avita, Retin-A, Tretin-X, Atralin)

Tretinoin inhibits microcomedo formation and eliminates existing lesions. It makes keratinocytes in sebaceous follicles less adherent and easier to remove. The drug is available as a 0.025%, 0.05%, or 0.1% cream and as a 0.01% or 0.025% gel.

 

Questions & Answers

Overview

What is necrobiosis lipoidica?

What causes necrobiosis lipoidica?

Which patient groups have the highest prevalence of necrobiosis lipoidica?

What is the prevalence of necrobiosis lipoidica in the US?

What is the prognosis of necrobiosis lipoidica?

Presentation

Which clinical history findings are characteristic of necrobiosis lipoidica?

Which physical findings are characteristic of necrobiosis lipoidica?

DDX

Which conditions should be included in the differential diagnoses of necrobiosis lipoidica?

What are the differential diagnoses for Necrobiosis Lipoidica?

Workup

What is the role of lab testing in the diagnosis of necrobiosis lipoidica?

Which histologic findings are characteristic of necrobiosis lipoidica?

Treatment

How is necrobiosis lipoidica treated?

What is the efficacy of topical treatments for necrobiosis lipoidica?

What is the role of surgery in the treatment of necrobiosis lipoidica?

What is the role of laser therapy in the treatment of necrobiosis lipoidica?

What is the role of antiplatelet aggregation therapy in the treatment of necrobiosis lipoidica?

What is the role of TNF-alpha inhibition in the treatment of necrobiosis lipoidica?

Medications

What is the efficacy of medications used in the treatment of necrobiosis lipoidica?

Which medications in the drug class Retinoid-like Agents, Topical are used in the treatment of Necrobiosis Lipoidica?

Which medications in the drug class Anticoagulants, Hematologic are used in the treatment of Necrobiosis Lipoidica?

Which medications in the drug class Immunomodulators are used in the treatment of Necrobiosis Lipoidica?

Which medications in the drug class B Vitamins are used in the treatment of Necrobiosis Lipoidica?

Which medications in the drug class Antiplatelet Agents are used in the treatment of Necrobiosis Lipoidica?

Which medications in the drug class Hemorheologic Agents are used in the treatment of Necrobiosis Lipoidica?