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Dermatology > METABOLIC DISEASES
Necrobiosis Lipoidica
Article Last Updated: Jan 25, 2007
AUTHOR AND EDITOR INFORMATION
Section 1 of 10  
Author: Cheryl J Barnes, MD, Director of Pediatric Dermatology, Associate Professor, Department of Internal Medicine, Division of Dermatology, Medical College of Georgia
Cheryl J Barnes is a member of the following medical societies: American Academy of Dermatology
Coauthor(s):
Loretta Davis, MD, Professor, Department of Internal Medicine, Division of Dermatology, Medical College of Georgia
Editors: Gregory J Raugi, MD, PhD, Professor, Department of Internal Medicine, Division of Dermatology, University of Washington at Seattle; Chief, Dermatology Section, Primary and Specialty Care Service, Veterans Administration Medical Center of Seattle; David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Director, Division of Dermatology, Scott and White Clinic; Director Dermatology Residency Training Program, Scott and White Clinic; Edward F Chan, MD, Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania School of Medicine; Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University; Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Author and Editor Disclosure
Synonyms and related keywords:
necrobiosis lipoidica diabeticorum, NLD, dermatitis atrophicans lipoidica diabetica, collagen degeneration, diabetic microangiopathy, vasculitis
Background
In 1929, Oppehhein first described necrobiosis lipoidica diabeticorum and called it dermatitis atrophicans lipoidica diabetica, but it was later renamed necrobiosis lipoidica diabeticorum (NLD) by Urbach in 1932. In 1935, Goldsmith reported the first case in a nondiabetic patient. Other cases of NLD 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 this disorder was suggested to exclude diabetes from the title. Today, the term necrobiosis lipoidica (NL) is used to encompass all patients with the same clinical lesions regardless of whether or not diabetes is present.
Pathophysiology
NL is a disorder of collagen degeneration with a granulomatous response, thickening of blood vessel walls, and fat deposition. The exact cause of NL is unknown, but the leading theory of NL has focused on diabetic microangiopathy. Other theories suggest trauma or inflammatory or metabolic changes. Still other theories suggest that an antibody-mediated vasculitis may cause the changes seen in NL.
Frequency
United States
NL has been described in about 0.3% of diabetic patients. In one study, NL 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 NL, while 25% of patients had lesions that appeared with the onset of diabetes mellitus. The presence or progression of NL does not correlate with how well the diabetes is controlled.
Mortality/Morbidity
Treatment for NL is not very satisfactory. The disease is typically chronic with variable progression and scarring. Squamous cell cancers have been reported in older lesions of NL related to previous trauma and ulceration.
Race
NL has been reported to occur in all races with no predilection.
Sex
NL is 3 times more common in women than in men.
Age
The average age of onset is 30 years, but it can occur at any age. The age of onset ranges from infancy to the eighth decade. NL tends to develop at an earlier age in patients with diabetes.
History
- Patients usually present with asymptomatic shiny 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.
- The clinical appearance of NL is distinctive, yet there are many atypical presentations and early forms can be hard to recognize.
- Superficial annular lesions can resemble granuloma annulare.
- Yellow annular lesions of NL with a fatty infiltration can resemble xanthomas.
- Necrobiotic xanthogranuloma (NXG) is a rare disease that can mimic NL clinically and histologically. NXG has been associated with paraproteinemia and some hematologic malignancies, which is not the case with NL.
- Sarcoidosis of the skin can appear like NL both clinically and histologically.
- Rheumatoid nodules also have a histologic appearance similar to NL but clinically appear like subcutaneous nodules rather than atrophic plaques.
- Ulcerated necrobiotic lesions also have been described in patients with rheumatoid arthritis.
Physical
- Skin lesions of classic NL begin as 1- to 3-mm well-circumscribed papules or nodules that expand with an active border to become waxy, atrophic, round plaques centrally. Initially, these plaques are red-brown in color but progressively become more yellow and atrophic in appearance.
- Most cases of NL 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 NL.
- The Koebner phenomenon has been well established in patients with NL, especially in patients with vasculitis at the site of trauma.
- Miller reported a case of a woman with known type 1 diabetes mellitus who developed biopsy-proven NL in a cholecystectomy scar and also on her abdomen at insulin injection sites.
- In most patients, the lesions of NL are typically multiple and bilateral. The lesions may become painless because of cutaneous nerve damage in 75% of the cases, or they can be extremely painful in 25% of the cases.
Causes
NL remains a disease of questionable etiology despite extensive studies. The pathogenesis has not been demonstrated to be linked to genetic factors.
- Because of the strong relationship between diabetes and NLD, 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 NL. A deposition of glycoprotein in blood vessel walls may be the cause of diabetic microangiopathy. A similar glycoprotein deposition is seen in NL.
- Another theory is based on the deposition of immunoglobulins, the third component of complement and fibrinogen in the blood vessel walls of patients with NL. Some believe an antibody-mediated vasculitis may initiate the blood vessel changes and subsequent necrobiosis in NL.
- An additional etiologic theory focuses on the abnormal collagen in NL. 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 NL.
- 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 NL.
Granuloma Annulare
Sarcoidosis
Xanthomas
Lab Studies
- Laboratory findings are not helpful in the diagnosis of NL. Some advocate checking for glucose intolerance to evaluate for the presence or absence of diabetes mellitus. NL has been the first sign of diabetes in some patients and a clue to possible diabetic potential in others.
Histologic Findings
Histopathologically, NL presents with interstitial and palisaded granulomas that involve the subcutaneous tissue and dermis. At low magnification, lesions of NL 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 NL.
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 NL has demonstrated immunoglobulin M, immunoglobulin A, C3, and fibrinogen in the blood vessels, which cause the vascular thickening. In nondiabetic patients with NL, the vascular changes are not as prominent.
Medical Care
Treatment for NL is not very effective partially because the exact etiology remains unknown.
- Because localized trauma can cause NL to ulcerate, protection of the legs with elastic support stockings and leg rest may be helpful.
- Topical and intralesional steroids can lessen the inflammation of early active lesions and the active borders of enlarging lesions, but these have little beneficial effect on atrophic lesions that are burned out. In fact, with atrophic lesions, steroid use may cause further atrophy.
- In 2005, Clayton and Harrison reported a case of ulcerated NL that was treated successfully with 0.1% topical tacrolimus ointment applied twice daily for 1 month. Tacrolimus is a calcineurin inhibitor that has been shown to have a mechanism of action similar to cyclosporine in that it prevents T-cell activation. Cyclosporine at doses of 2.5 mg/kg/d has also been used with success in treating ulcerated NL.
- Antiplatelet aggregation therapy with aspirin and dipyridamole has been tried because it was believed that NL was caused by platelet-mediated vascular occlusion or immune mechanisms that altered platelet survival. These drugs are believed to prolong platelet survival time and, hence, prevent further worsening of NL. The results of double-blind studies with aspirin and dipyridamole have varied but overall have shown some beneficial effects. Littler et al reported a case of NL that was treated successfully with pentoxifylline, a drug used in the treatment of intermittent claudication. Pentoxifylline is believed to decrease blood viscosity by increasing fibrinolysis and red blood cell deformity. It also inhibits platelet aggregation.
- In several case reports, tumor necrosis factor (TNF) agents such as etanercept and infliximab were been shown to improve chronic granulomatous skin disorders. Infliximab is a chimeric monoclonal antibody and acts to inhibit tumor necrosis factor-alpha. TNF-alpha has a potentially critical role in conditions such as disseminated granuloma annulare and NL. It is found in high concentrations in the sera and skin in patients with these conditions. Kolde et al reported infliximab as a successful treatment option for ulcerated NL. Thalidomide has anti-TNF effects and has also been reported as successful therapy.
- Spencei et al recently described a case of ulcerated NL that was treated successfully with topically applied bovine collagen. Collagen is believed to improve granulation tissue by supporting fibroblast activity and promoting wound debridement by increasing the number of macrophages and neutrophils at the wound site.
- De Rie et al reported successful treatment with topical psoralen plus UV-A light therapy. Thirty patients were treated with twice-weekly courses of topical psoralen plus UV-A 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 as successful.
- Ticlopidine, nicotinamide, clofazimine, and perilesional heparin injections have been used in uncontrolled studies and appeared to benefit some patients with NL.
- According to W.R. Heymann, tretinoin has been used to diminish the atrophy associated with NL (personal communication).
Surgical Care
- Excision and grafting have been successful, but recurrence may occur secondary to the underlying vascular damage. Poor healing of the graft site is not uncommon.
- Laser care is also described. Moreno-Arias and Camps-Fresneda treated NL with a pulse dye laser (Candela SPTL; Irvine, Mass). 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.
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
Drug Category: Hemorheologic agents
Reduce complications resulting from increased blood viscosity.
| Drug Name | Pentoxifylline (Trental) |
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| Description | May alter rheology of red blood cells, which, in turn, reduces blood viscosity. Increases fibrinolysis and red blood cell deformity. Also inhibits platelet aggregation. |
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| Adult Dose | 400 mg PO tid with meals; may reduce frequency to bid if GI or CNS adverse effects occur |
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| Pediatric Dose | Not established |
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| Contraindications | Documented hypersensitivity; cerebral and/or retinal hemorrhage |
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| Interactions | Coadministration with cimetidine or theophylline increases effects/toxic potential; increases effect of antihypertensives |
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| Pregnancy | C - Safety for use during pregnancy has not been established.
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| Precautions | Caution in renal impairment |
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Drug Category: Antiplatelet agents
Inhibit platelet aggregation.
| Drug Name | Ticlopidine (Ticlid) |
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| Description | Second-line antiplatelet therapy for patients who fail aspirin therapy. |
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| Adult Dose | 250 mg PO bid |
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| Pediatric Dose | Not established |
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| Contraindications | Documented hypersensitivity; neutropenia or thrombocytopenia; liver damage; active bleeding disorders |
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| Interactions | Effects may decrease with coadministration of corticosteroids and antacids; toxicity increases when taken concurrently with theophylline, cimetidine, aspirin, and NSAIDs |
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| Pregnancy | B - Usually safe but benefits must outweigh the risks.
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| Precautions | Discontinue if absolute neutrophil count decreases to <1200/µL or if platelet count falls to <80,000/µL |
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Drug Category: Antihyperlipidemic agents
Can reduce blood lipids.
| Drug Name | Niacin (Nicotinamide, Nicobid, Nicolar) |
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| Description | Source of niacin used in tissue respiration, lipid metabolism, and glycogenolysis. |
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| Adult Dose | 1.5-6 g/d divided tid |
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| Pediatric Dose | Not established |
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| Contraindications | Documented hypersensitivity; active liver disease or unexplained, significant increases in AST and ALT; large doses of niacin, especially when administered in SR form (associated with severe hepatotoxicity); definite and recent history of peptic ulcer disease (can reactivate ulcers) |
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| Interactions | Cutaneous vasodilation may be a problem if high-dose used with peripheral dilators such as nitroglycerin; taking aspirin 30-60 min before first dose of day may help alleviate prostaglandin-mediated adverse effects (eg, flushing, itching); clonidine may inhibit niacin-induced flushing |
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| Pregnancy | A - Safe in pregnancy
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| Precautions | Pregnancy category C when used at doses greater than RDA; caution in gallbladder disease or diabetes and those predisposed to gout; monitor blood glucose; may elevate uric acid levels |
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Drug Category: Leprostatic agents
May have immunomodulatory effects.
| Drug Name | Clofazimine (Lamprene) |
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| Description | Inhibits mycobacterial growth, binds preferentially to mycobacterial DNA. Has antimicrobial properties, but mechanism of action is unknown. |
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| Adult Dose | 100 mg/d PO qd |
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| Pediatric Dose | 1 mg/kg/d PO qd |
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| Contraindications | Documented hypersensitivity |
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| Interactions | Dapsone may inhibit anti-inflammatory activity of clofazimine |
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| Pregnancy | C - Safety for use during pregnancy has not been established.
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| Precautions | Severe abdominal symptoms may require exploratory laparotomies; caution in patients with GI problems (eg, abdominal pain, diarrhea); skin discoloration due to drug may result in depression or suicide; apply oil to skin for dryness and ichthyosis |
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Drug Category: Anticoagulants
Inhibit formation of blood clots resulting from blood disorders.
| Drug Name | Heparin |
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| Description | Augments activity of antithrombin III and prevents conversion of fibrinogen to fibrin. Does not actively lyse but can inhibit further thrombogenesis. Prevents reaccumulation of clot after spontaneous fibrinolysis. |
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| Adult Dose | Initial dose: 40-170 U/kg IV
Maintenance infusion: 18 U/kg/h IV; alternatively, 50 U/kg/h IV initially, followed by continuous infusion of 15-25 U/kg/h; increase dose by 5 U/kg/h q4h prn using PTT results |
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| Pediatric Dose | Initial dose: 50 U/kg IV
Maintenance infusion: 15-25 U/kg/h IV; increase dose by 2-4 U/kg/h q6-8h prn using PTT results |
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| Contraindications | Documented hypersensitivity; subacute bacterial endocarditis; active bleeding; history of heparin-induced thrombocytopenia |
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| Interactions | Digoxin, nicotine, tetracycline, and antihistamines may decrease effects; NSAIDs, aspirin, dextran, dipyridamole, and hydroxychloroquine may increase heparin toxicity |
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| Pregnancy | C - Safety for use during pregnancy has not been established.
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| Precautions | In neonates, preservative-free heparin is recommended to avoid possible toxicity (gasping syndrome) by benzyl alcohol, which is used as preservative; caution in severe hypotension and shock; monitor for bleeding in peptic ulcer disease, menstruation, increased capillary permeability, and when giving IM injections |
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Drug Category: Retinoids
Regulate cell growth and differentiation.
| Drug Name | Tretinoin (Avita, Retin-A) |
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| Description | Inhibits microcomedo formation and eliminates lesions present. Makes keratinocytes in sebaceous follicles less adherent and easier to remove. Available as 0.025%, 0.05%, and 0.1% creams. Available also as 0.01% and 0.025% gels. |
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| Adult Dose | Begin with lowest tretinoin formulation and increase as tolerated; apply hs or qod; lower frequency of application if irritation develops |
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| Pediatric Dose | <12 years: Not established
>12 years: Administer as in adults |
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| Contraindications | Documented hypersensitivity |
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| Interactions | Toxicity increases with coadministration of benzoyl peroxide, salicylic acid, and resorcinol; avoid topical sulfur, resorcinol, salicylic acid, other keratolytics, abrasives, astringents, spices, and lime |
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| Pregnancy | C - Safety for use during pregnancy has not been established.
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| Precautions | Photosensitivity may occur with excessive sunlight exposure; caution in eczema; do not apply to mucous membranes, mouth, and angles of nose |
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Complications
- The main complication of NL 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 NL.
Prognosis
- From a cosmetic standpoint, the prognosis of NL 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.
| Media file 1:
Typical presentation of necrobiosis lipoidica on the lower pretibial legs. |
 |  View Full Size Image | |
Media type: Photo
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| Media file 2:
Red-brown plaque with yellow atrophic center on lower leg. |
 | View Full Size Image | |
Media type: Photo
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- Beattie PE, Dawe RS, Ibbotson SH, Ferguson J. UVA1 phototherapy for treatment of necrobiosis lipoidica. Clin Exp Dermatol. Mar 2006;31(2):235-8. [Medline].
- Braverman IM. Cutaneous manifestations of diabetes mellitus. Med Clin North Am. Jul 1971;55(4):1019-29. [Medline].
- Clayton TH, Harrison PV. Successful treatment of chronic ulcerated necrobiosis lipoidica with 0.1% topical tacrolimus ointment. Br J Dermatol. Mar 2005;152(3):581-2. [Medline].
- Clement M, Guy R, Pembroke AC. Squamous cell carcinoma arising in long-standing necrobiosis lipoidica. Arch Dermatol. Jan 1985;121(1):24-5. [Medline].
- De Rie MA, Sommer A, Hoekzema R, Neumann HA. Treatment of necrobiosis lipoidica with topical psoralen plus ultraviolet A. Br J Dermatol. Oct 2002;147(4):743-7. [Medline].
- Eldor A, Diaz EG, Naparstek E. Treatment of diabetic necrobiosis with aspirin and dipyridamole. N Engl J Med. May 4 1978;298(18):1033. [Medline].
- Engel MF, Smith JG Jr. The pathogenesis of necrobiosis lipoidica. Necrobiosis lipoidica, a form fruste of diabetes mellitus. Arch Dermatol. Nov 1960;82:791-7. [Medline].
- Hamlin CR, Kohn RR, Luschin JH. Apparent accelerated aging of human collagen in diabetes mellitus. Diabetes. Oct 1975;24(10):902-4. [Medline].
- Handfield-Jones S, Jones S, Peachey R. High dose nicotinamide in the treatment of necrobiosis lipoidica. Br J Dermatol. May 1988;118(5):693-6. [Medline].
- Heidenheim M, Jemec GB. Successful treatment of necrobiosis lipoidica diabeticorum with photodynamic therapy. Arch Dermatol. Dec 2006;142(12):1548-50. [Medline].
- Heymann WR. Necrobiosis lipoidica treated with topical tretinoin. Cutis. Jul 1996;58(1):53-4. [Medline].
- Jetton RL, Lazarus GS. Minidose heparin therapy for vasculitis of atrophie blanche. J Am Acad Dermatol. Jan 1983;8(1):23-6. [Medline].
- Kolde G, Muche JM, Schulze P, et al. Infliximab: a promising new treatment option for ulcerated necrobiosis lipoidica. Dermatology. 2003;206(2):180-1. [Medline].
- Kukreja T, Petersen J. Thalidomide for the treatment of refractory necrobiosis lipoidica. Arch Dermatol. Jan 2006;142(1):20-2. [Medline].
- Lim C, Tschuchnigg M, Lim J. Squamous cell carcinoma arising in an area of long-standing necrobiosis lipoidica. J Cutan Pathol. Aug 2006;33(8):581-3. [Medline].
- Littler CM, Tschen EH. Pentoxifylline for necrobiosis lipoidica diabeticorum. J Am Acad Dermatol. Aug 1987;17(2 Pt 1):314-6. [Medline].
- Marr TJ, Traisman HS, Griffith BH, Schafer MA. Necrobiosis lipoidica diabeticorum in a juvenile diabetic: treatment by excision and skin grafting. Cutis. Mar 1977;19(3):348-50. [Medline].
- Mensing H. [Clofazimine--therapeutic alternative in necrobiosis lipoidica and granuloma anulare]. Hautarzt. Feb 1989;40(2):99-103. [Medline].
- Miller RA. The Koebner phenomenon. Int J Dermatol. May 1982;21(4):192-7. [Medline].
- Moreno-Arias GA, Camps-Fresneda A. Necrobiosis lipoidica diabeticorum treated with the pulsed dye laser. J Cosmet Laser Ther. Sep 2001;3(3):143-6. [Medline].
- Muller SA. Dermatologic disorders associated with diabetes mellitus. Mayo Clin Proc. Oct 1966;41(10):689-703. [Medline].
- Muller SA, Winkelmann RK. Necrobiosis lipoidica diabeticorum histopathologic study of 98 cases. Arch Dermatol. Jul 1966;94(1):1-10. [Medline].
- Rhodes EL. Necrobiosis lipoidica treated with ticlopidine. Acta Derm Venereol. 1986;66(5):458. [Medline].
- Rollins TG, Winkelmann RK. Necrobiosis lipoidica granulomatosis. Necrobiosis lipoidica diabeticorum in the nondiabetic. Arch Dermatol. Oct 1960;82:537-43. [Medline].
- Soler NG, McConnachie PR. HLA antigens and necrobiosis lipoidica diabeticorum--a comparison between insulin-dependent diabetics with and without necrobiosis. Postgrad Med J. Dec 1983;59(698):759-62. [Medline].
- Spenceri EA, Nahass GT. Topically applied bovine collagen in the treatment of ulcerative necrobiosis lipoidica diabeticorum. Arch Dermatol. Jul 1997;133(7):817-8. [Medline].
- Stanway A, Rademaker M, Newman P. Healing of severe ulcerative necrobiosis lipoidica with cyclosporin. Australas J Dermatol. May 2004;45(2):119-22. [Medline].
- Stawiski MA, Voorhees JJ. Cutaneous signs of diabetes mellitus. Cutis. Sep 1976;18(3):415-21. [Medline].
- Ullman S, Dahl MV. Necrobiosis lipoidica. An immunofluorescence study. Arch Dermatol. Dec 1977;113(12):1671-3. [Medline].
- Wake N, Fang JC. Images in clinical medicine. Necrobiosis lipoidica diabeticorum. N Engl J Med. Nov 2 2006;355(18):e20. [Medline].
- Zeichner JA, Stern DW, Lebwohl M. Treatment of necrobiosis lipoidica with the tumor necrosis factor antagonist etanercept. J Am Acad Dermatol. Mar 2006;54(3 Suppl 2):S120-1. [Medline].
Necrobiosis Lipoidica excerpt Article Last Updated: Jan 25, 2007
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