Diabetic Man With Pruritic Pretibial Rash

HISTORY

A 69-year-old man seen because of a pruritic pretibial rash of 3 months' duration. The rash started as reddish brown papules that slowly enlarged and changed.

He has had type 2 diabetes mellitus for 10 years, treated with metformin, 500 mg bid, and has fairly good glycemic control. he does not smoke, and his past health otherwise unremarkable.

PHYSICAL EXAMINATION

Several well circumscribed, brownish plaques are observed in the left pretibial area. Borders are somewhat raised, a bit firm, and more deeply pigmented than centers. Central atrophy with depression below the level of the skin surface is noted in some lesions.

Physical examination apart from the skin is normal.
 

WHAT'S YOUR DIAGNOSIS?

(Answer and discussion on next page)

ANSWER: NECROBIOSIS LIPOIDICA DIABETICORUM

This patient's shin shows mildly atrophic skin, marked by the paucity of skin lines and an impression that the venous network is unduly prominent beneath the surface, though not dilated. In addition, partial confluence of 2 large circular red-brown lesions is seen, the rightmost "dribbling" down the lateral margin toward the ankle.

Necrobiosis lipoidica diabeticorum (NLD) is characterized at the bedside by ovoid plaques with an irregular, elevated periphery and an atrophic center.¹ The condition was first described by Oppenheim in 1929.² The term "necrobiosis lipoidica diabeticorum" was based on characteristic histologic findings and frequent association with diabetes mellitus.³

EPIDEMIOLOGY

NLD is an uncommon but well-recognized complication of diabetes mellitus, with a prevalence of 0.3% in diabetic adults and 0.06% in diabetic children.^4,5 Some three fourths of persons with NLD have diabetes at the time of diagnosis.⁶ In others, these lesions precede the diagnosis of diabetes by up to several years.⁷

A family history of diabetes can be obtained in 90% of affected patients.⁸ The female to male ratio is approximately 4:1. The cause of the sex disparity is unknown.¹ NLD usually arises in young or middle adulthood.^8,9 Smoking increases the risk of NLD.⁷ The condition is also more prevalent among those with thyroid disease, Crohn disease, and ulcerative colitis.^6,10,11

PATHOGENESIS

Although the etiology and mechanism of development remain unknown, diabetic microangiopathy might be a major underlying cause.^4,8 In this regard, persistent microalbuminuria and retinopathy are more common among patients with diabetes in whom NLD develops than among control patients with diabetes who do not have NLD.¹² However, this could merely reflect that persistent microalbuminuria and retinopathy imply long disease duration and poor diabetic control: NLD may also be associated with these factors.^12,13

Just to make it more confusing, other groups with severe microvasculopathy--including those with uremic arteriolopathy (calciphylaxis)¹⁴--do not characteristically have NLD. Nor is NLD typical of some other vaso-occlusive disorders, such as atheroembolic disease,¹⁵ vasculitides,^16-18 or the lupus "anticoagulant." Insights about the pathogenesis of NLD are empiric, limited, and imprecise. One struggles to explain why young diabetics are preferentially affected by NLD, whereas older diabetics--precisely those persons with the worst vasculopathy--constitute a lower-risk population.

Immunoglobulins have been found around blood vessels in affected areas. This could suggest an immune complex vasculitis,^19,20 except that vasculitis is not seen in biopsy specimens. Focal degeneration of collagencould also be an initiating event.^21-23 In one study, levels of lysyl oxidase (which produces collagen cross-linking by the oxidation of lysine and hydroxylysine) were elevated in patients with NLD.²¹ In another study, overhydration of collagen was demonstrated in the skin of diabetics, but the relationship between hydration of these fibers and NLD is obscure.²²

HISTOLOGY

Histologically, the characteristic features include necrobiosis, which is a brightly eosinophilic degeneration of collagen, throughout the skin, and infiltration of collagen bundles by palisading histiocytes--a term that describes how they align with the nuclei in a single parallel axis.^1,8 The upper dermis contains fatty deposits.¹ Mucin deposits are minimal.⁸ Although NLD is considered a granulomatous and inflammatory disorder, the significance of the histiocytes is uncertain, as is the paucity of more common inflammatory cells, such as lymphocytes or neutrophils.

CLINICAL MANIFESTATIONS

NLD usually begins as erythematous papules. These gradually enlarge, then develop irregular margins, and can coalesce into irregular waxy plaques (Figure 1). The plaques often display a yellowish or reddish brown hue and tend to be sharply demarcated, with raised and sometimes indurated borders that could at least transiently suggest an enlarging skin cancer. Some of the lesions may show central atrophy, telangiectasia, and yellow pigmentation.²⁴ In 85% of cases, the lesion is confined to the pretibial area.^4,25 Ankles, feet, calves, and thighs are most often involved, along with the shins, in the remainder. In fewer than 2% of cases, lesions are found in other areas but not the legs.²²

Most NLD lesions are asymptomatic. Some lesions are pruritic (as were those in our patient), painful, or dysesthetic.⁷ Ulceration develops in one third of cases.²⁶ Ulcers are typically caused by minor trauma; healing is notoriously slow, and not because of any superinfection,²⁶ although terrible-looking infection can occur (Figure 2). Curiously, the ulcerations do not appear to represent simple venous disease superimposed on NLD, although any condition that preferentially affects the shin will make one wonder about venous insufficiency.

DIFFERENTIAL DIAGNOSIS

On a first viewing, one might think of the brown discoloration of tinea, an impression augmented by variable erythema and a partly serpiginous border. Given this particular appearance, it would not be unreasonable to attempt a course of topical antifungal therapy on part or all of the lesion, and to confirm one's tentative diagnosis of NLD in part by a lack of response to this intervention. Another condition likely to come to mind is the irregular brown-staining of dermatitis venosa, based on tiny cutaneous hemorrhages to which the host is predisposed by a locally elevated capillary pressure, with slow resorption of the hemosiderin that results from degradation of hemoglobin and polymerization of the residues. Since venous disease is exceptionally common and can coexist with NLD, one would look for a more irregular distribution of pigment, as here, to help rule out a venous element. A lack of distended leg veins on standing would enhance this impression.

The differential diagnosis of these lesions includes such conditions as pretibial myxedema (based on location, if nothing else)²⁷; pyoderma gangrenosum, which tends to be both more violaceous and more purulent-looking; granuloma annulare; diabetic dermopathy; and necrobiotic xanthogranuloma.

Classically, granuloma annulare presents as asymptomatic erythematous, dome-shaped papules arranged in a circle around a central depression.²⁸ The sites most commonly affected are the dorsa of hands and feet, ankles, and elbows, so that NLD falls sharply from the differential diagnosis based on pattern of distribution.²⁸ Histologically, collagen degeneration and histiocytic palisading are shared with NLD, but abundant mucin deposits help to distinguish granuloma annulare from NLD.^1,8

Diabetic dermopathy (spotted leg syndrome or shin spots) is the most common cutaneous manifestation of diabetes.^1,29 Diabetic dermopathy presents as multiple atrophic brown macules and at most sparse, small patches in the pretibial areas, so that the present case would not justify this diagnosis. The condition is more prevalent in males.

Necrobiotic xanthogranuloma typically presents as multiple asymptomatic indurated papulonodules or plaques with a yellow xanthomatous hue.³⁰ The periorbital area is selectively involved, so that the clinical differential diagnosis may be xanthelasma rather than NLD. About 90% of persons with necrobiotic xanthogranuloma have a paraproteinemia and many have cryoglobulinemia. Affected persons are at risk for plasma cell dyscrasias and lymphoproliferative disorders.³⁰

TREATMENT

NLD lesions are usually self-limited.⁸ However, they may recur.³¹ Even in those that become ulcerated, infection is rare.³² Skin cancers have been reported in chronically ulcerated NLD lesions as in other kinds of nonhealing ulcers, but this is very rare.

Because of the unsightliness of NLD lesions and concerns about potential infection or neoplasia, diverse treatments have been tried, without consistent benefit.^33-35 These include topical, intralesional, or systemic corticosteroids, topical retinoids, the combination of aspirin and the older antianginal/antiplatelet agent dipyridamole), and even cyclosporin. Recently, all patients in a small group of young and middle aged women with NLD benefited from psoralen and ultraviolet A light (PUVA).³⁶

"What's Your Diagnosis?" last reviewed NLD almost exactly 1 decade ago.³² Enough has changed that this revisit feels essential as we all pursue the ongoing effort to stay up to date.

Leung AKC, Fincati M, Schneiderman H. Necrobiosis lipoidica diabeticorum: a clearly described but poorly understood entity with confusing predilection for younger adult diabetics. CONSULTANT. 2005;45:1007-1014.

References

1.Aye M, Masson EA. Dermatological care of the diabetic foot. Am J Clin Dermatol. 2002;3:463-474.
2. Oppenheim M. Uber eine bisher nicht beschriebene, mit eigentumlicher lipoider Degeneration der Elastica und des Blindegewebes einhergehende chronische Dermatose bei Diabetes Mellitus. Arch Derm Syph. 1932;166: 576-583.
3. Urbach E. Beitrage zu einer physiologischen und pathologischen Chemie der Haut; eine neue diabetische Stoffwechseldermatose: Nekrobiosis lipoidica diabeticorum. Arch Derm Syph. 1932;166:273-285.
4. Gebauer K, Armstrong M. Koebner phenomenon with necrobiosis lipoidica diabeticorum. Int J Dermatol. 1993;32:895-896.
5. De Silva BD, Schofield OM, Walker JD. The prevalence of necrobiosis lipoidica diabeticorum in children with type 1 diabetes. Br J Dermatol. 1999; 141:593-594.
6. Murray CA, Miller RA. Necrobiosis lipoidica diabeticorum and thyroid disease. Int J Dermatol. 1997;36:799-800.
7. Kelly WF, Nicholas J, Adams J, et al. Necrobiosis lipoidica diabeticorum: association with background retinopathy, smoking, and proteinuria. A case controlled study. Diabet Med. 1993;10:725-728.
8. Sibbald RG, Landolt SJ, Toth D. Skin and diabetes. Endocrinol Metab Clin North Am. 1996;25:463-472.
9. Pestoni C, Ferreiros MM, de la Torre C, et al. Two girls with necrobiosis lipoidica and type I diabetes mellitus with transfollicular elimination in one girl. Pediatr Dermatol. 2003;20:211-214.
10. Du Boulay C, Whorwell PJ. "Nodular necrobiosis": a new cutaneous manifestation of Crohn's disease? Gut. 1982;23:712-715.
11. Whorwell PJ, Haboubi NY, Du Boulay C. Nodular necrobiosis in association with ulcerative colitis. Gut. 1986;27:1517.
12. Verrotti A, Chiarelli F, Amerio P, et al. Necrobiosis lipoidica diabeticorum in children and adolescents: a clue for underlying renal and retinal disease. Pediatr Dermatol. 1995;12:220-223.
13. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993; 329:977-986.
14.Schneiderman H, Yun HC. Calcific uremic arteriolopathy (calciphylaxis). Consultant. 2000;40:539-541.
15. Schneiderman H. Atheromatous emboli and livedo. Consultant. 1992;32(9): 73-76.
16.Melikoglu M, Apaydin S, Hamuryudan V, et al. Calciphylaxis: a condition mimicking necrotizing vasculitis. Clin Rheumatol. 1996;15:498-500.
17.Young DK, Burton MF, Herman JH. Multiple cholesterol emboli syndrome simulating systemic necrotizing vasculitis. J Rheumatol. 1986;13:423-426.
18. Richards AM, Eliot RS, Kanjuh VI, et al. Cholesterol embolism: a multiple-system disease masquerading as polyarteritis nodosa. Am J Cardiol. 1965;15:696-707.
19. Lowitt MH, Dover JS. Necrobiosis lipoidica. J Am Acad Dermatol. 1991; 25(5 pt 1):735-748.
20. Dahl MV. Immunofluorescence, necrobiosis lipoidica, and blood vessels. Fluorescent lights in the tunnels. Arch Dermatol. 1988;124:1417-1419.
21. Yuen CT, Easton D, Misch KJ, et al. Increased activity of serum amine oxi-dases in granuloma annulare, necrobiosis lipoidica and diabetes. Br J Dermatol. 1987;116:643-649.
22. Eaton RP. The collagen hydration hypothesis: a new paradigm for the secondary complications of diabetes mellitus. J Chronic Dis. 1986;39:763-766.
23. Imakado S, Satomi H, Iskikawa M, et al. Diffuse necrobiosis lipoidica diabeticorum associated with non-insulin dependent diabetes mellitus. Clin Exp Dermatol. 1998;23:271-273.
24. Jabbour SA. Cutaneous manifestations of endocrine disorders: a guide for dermatologists. Am J Clin Dermatol. 2003;4:315-331.
25. Yorav S, Feinstein A, Ziv R, et al. Diffuse necrobiosis lipoidica diabeticorum. Cutis. 1992;50:68-69.
26. Spenceri EA, Nahass GT. Topically applied bovine collagen in the treatment of ulcerative necrobiosis lipoidica diabeticorum. Arch Dermatol. 1997;133:817-819.
27. Ramakrishnan N, Schneiderman H. Pretibial myxedema and its association with thyroid disorders. Consultant. 1996;36:309-310.
28.Leung AKC, Rafaat M. Granuloma annulare. Can J Diagn. 2001;18:175-176.
29.Rosen T. Shin spots and other cutaneous manifestations of diabetes mellitus. Consultant. 1991;31(4):57-60.
30.Goodman WT, Barrett TL. Necrobiotic xanthogranuloma. In: Bolognia JL, Jorizzo JL, Rapini RP, et al, eds. Dermatology. Edinburgh: Mosby; 2003;1438-1439.
31.Yigit S, Estrada E. Recurrent necrobiosis lipoidica diabeticorum associated with venous insufficiency in an adolescent with poorly controlled type 2 diabetes mellitus. J Pediatr. 2002;141:280-282.
32. Ramakrishnan N, Schneiderman H. Necrobiosis lipoidica and its associations. Consultant. 1996;36:1011-1013.
33.Petzelbauer P, Wolff K, Tappeiner G. Necrobiosis lipoidica: treatment with systemic corticosteroids. Br J Dermatol. 1992;126:542-545.
34.Heymann WR. Necrobiosis lipoidica treated with topical tretinoin. Cutis. 1996;58:53-54.
35.Statham B, Finlay AY, Marks R. A randomized double blind comparison of an aspirin dipyridamole combination versus a placebo in the treatment of necrobiosis lipoidica. Acta Derm Venereol. 1981;61:270-271.
36. Ling TC, Thomson KF, Goulden V, et al. PUVA therapy in necrobiosis lipoidica diabeticorum. J Am Acad Dermatol. 2002;46:319-320.