One-third of the 17 million patients with diabetes develop manifestations of the disease that affect their skin.^1,2 The cutaneous manifestations and signs of diabetes can heighten the suspicions of the practitioner regarding the diagnosis of these skin conditions. Patients with diabetes who have peripheral sensory neuropathy and impaired circulation are at an increased risk of developing complications from skin and nail conditions like onychomycosis.³ These skin changes of the foot can lead to the formation of a diabetic foot ulcer and potentially limb-threatening infections. There are four categories of skin manifestations in diabetes: skin changes associated with diabetes, cutaneous manifestations of diabetes, cutaneous infections and skin reactions to anti-diabetic treatments. In order to recognize these manifestations and arrive at an appropriate treatment course, one must have a strong grasp of the various ways that diabetes can affect the skin and the lower extremities (see “Understanding How Diabetes Affects The Skin Of The Foot” below). Understanding How Diabetes Affects The Skin Of The Foot Diabetes affects the skin and lower extremities in many ways. Glucose comprises between 35 to 65 percent of the blood in the human epidermis. The transport of glucose into epidermal cells is not dependent on insulin but requires hexokinase and glucose-C-phosphate. The resulting elevated ratio of glucose in the epidermis of diabetic patients does not seem to have a pathological effect with the exception of potentating skin infections with saprophytic organisms like Candida albicans.⁴ Poor blood glucose control increases the risk for skin and foot manifestations and cutaneous complications with diabetes, and can compromise a patient’s vascular system.⁵ Researchers have shown that peripheral vascular disease is associated with diabetes.⁶ Arteriosclerosis of the arteries of the legs results in generalized cutaneous skin changes that may include a waxy appearance, atrophy, a loss of hair growth, skin temperature cooling at the distal digits, nail dystrophy, pallor on elevation and mottling on dependence.⁷ A reliable sign of large vessel disease is dependent rubor with a delayed return of color greater or equal to 15 seconds after one has applied pressure to the skin.⁸ Almost all patients with diabetes have capillary basement membrane thickening. However, this does not lead to occlusive microvascular lesions in and of itself.⁹ Thickening of the vessel walls with perivascular deposition of PAS-positive material and clumping of elastic fibers in the upper dermis are the most prominent histopathologic markers in diabetic skin.⁴ The signs of microangiopathy may include cutaneous reactive hyperemia and reduced capillary flow. The nail changes associated with microangiopathy include Beau’s lines, pterygium, proximal fold capillary microscopic changes, splinter hemorrhages and yellow nail discoloration.^7,10 Pertinent Pointers On Treating Xerosis Generalized xerosis or dry skin is one of the most common skin conditions one will see among patients who have type 2 diabetes. It is particularly prevalent among elderly patients. At times, the foot may become very dry, leading to peeling and cracking. The problem arises with the nerves that control the oil and moisture in the foot. Sebaceous and sweat glands maintain skin lubrication. The glands become atrophied in the presence of autonomic neuropathy. Another reason for dryness is the redistribution of blood flow in the soles by persistent and inappropriate dilatation of arteriovenous shunts. This activity diverts blood away from the skin surface. When this occurs in combination with alterations in the elasticity of the skin (due to non-enzymatic glycosylation of structural proteins and glycoproteins), the skin splits and portals for bacteria are created. Both pruritis and a sensation of burning usually accompany xerosis as principal symptoms. Structural changes occur among the aligned parallel corneocytes in normal skin as a result of xerosis.¹¹ A roughened epidermal surface results from the disruption of these cells. The progression of xerosis follows a defined pattern. Initially, the skin becomes dry and rough with pronounced skin lines. As the condition progresses, superficial scaling with fissuring and erythema develops. As a result of xerosis, the skin loses its flexibility. Therefore, it is less elastic and loses its ability to withstand trauma, which may result in skin breakdown, leading to a variety of infections. Practitioners can assist these patients by choosing an agent to maintain skin moisture. One should avoid recommending products that contain alcohol because they evaporate and their drying action compounds the original problem. Petroleum based products seal the skin surface and prevent what little lubrication is made from evaporating, but they do not penetrate the surface of the skin and do not replace skin moisture. Alpha hydroxy acids are frequently used to treat xerosis. Alpha hydroxy acids include glycolic, citric, lactic, mandelic and tartaric acid. Through a chemical process, these acids accelerate the softening of the skin, dissolving or peeling the outer layer of the skin to help maintain the skin’s capability to hold moisture. Lactic acid in concentrations of 2.5 percent to 12 percent is the most common alpha hydroxy acid used for moderate to severe xerosis. When treating patients who have neuropathic disease, one should exercise caution with creams that contain high concentrations of either urea or acetylsalicylic acid, given the corrosive nature of these creams. While application of topical emollient creams may not prevent the skin’s deterioration, the application process does facilitate regular inspection of the feet among patients with diabetes. A Helpful Primer On Diabetic Thick Skin, Yellow Skin, Diabetic Dermopathy And Diabetic Anhidrosis The prevalence of cutaneous disorders does not seem to differ between type 1 and type 2 diabetic patients. However, patients with type 2 diabetes do develop more frequent cutaneous infections whereas patients with type 1 diabetes develop more autoimmune-type cutaneous lesions.^12-14 Indeed, there are a number of pathognomonic cutaneous manifestations of diabetes (see “Cutaneous Manifestations Associated With Diabetes Mellitus” below). Diabetic thick skin. It has been demonstrated by ultrasound and reported by Huntley and Walter that patients with diabetes have thicker skin than those patients without diabetes.¹⁵ The pathogenesis of diabetic thick skin has not clearly been defined. There are three categories of diabetic thick skin: scleroderma-like changes of the hand associated with stiff joints and limited mobility; measurable skin thickness that is clinically insignificant and scleredema diabeticorum. There are distinct light and electron microscopic features that can help differentiate between diabetic thick skin and scleroderma. The collagen fibers of diabetic thick skin are seldom below 60 nm and there is no bimodality of the fibers.¹⁶ Researchers have proposed potential explanations for diabetic thick skin that include the hydration of collagen secondary to polyol accumulation and nonenzymatic glycosylation of collagen.^2,17 Yellow skin. Yellow nails and skin are a benign condition of the skin associated with diabetes. Its cause remains controversial and may be due to nonezymatic glycosylation of dermal collagen or elevated levels of carotene. This characteristic color of yellow skin may be the result of an accumulation of 2-(2-furoyl) 4(5)-(2-furanyl)-1H-imidazole, an end product of glycosylation that has a yellow hue.^2,18 One may see this yellow color on the palms of the hands, soles of the feet and the distal nail plate of the hallux.^2,18 Diabetic dermopathy. This is the most common cutaneous finding in diabetes and is also known as shin spots or spotted leg syndrome. Its incidence ranges from 30 to 60 percent among patients with diabetes.^2,4,7,12,19 Shermer, et. al., reported an incidence of 40 percent among diabetic patients in an Israeli hospital.²⁰ The condition is predominately seen in men over the age of 50. It appears as round to oval atrophic, hyperpigmented (brown) raised lesions on the pretibial areas of the lower extremities. They are usually multiple brown atrophic spots resembling large freckles. These lesions present with a symmetrical distribution and are usually bilateral. Older lesions may persist or disappear while new lesions appear. Histological studies of the lesions reveal edema of the papillary dermis, thickening of superficial blood vessels, mild lymphocytic infiltration and extravasations of erythrocytes.^2,21,22 These erythrocytes leave hemosiderin deposits, which result in brownish hyperpigmentation. Currently, there is no formal treatment for diabetic dermopathy because these lesions resolve spontaneously although they do leave scars.² No treatment is necessary and these lesions persist indefinitely. Diabetic anhidrosis. This cutaneous manifestation is related to diabetic autonomic neuropathy. A lesion in the sympathetic nerve supply to the skin has been identified as the principal cause. How To Identify Diabetic Bullae Diabetic bullae. Approximately 0.5 percent of diabetic individuals develop diabetic bullae or bullosis diabeticorum. These bullae have only been reported in adults between the ages of 40 and 70.¹² The blisters occur spontaneously without trauma and most are non-scarring.2 They are painless bullae on a non-inflammed base. They occur suddenly and are confined to the patient’s distal extremities (hands and feet). Bullae most commonly appear on the dorsum and sides of the lower legs and feet. The pathogenesis of these lesions has not yet been clearly been elaborated. There are three types of diabetic bullae. The first and most common presenting bullae are sterile and contain fluid. This type of bullae heals without scarring. Histological findings reveal intraepidermal cleavage without acantholysis.⁸ The second type of bullae is hemorrhagic and unfortunately heals with scarring. Histological studies depict cleavage below the dermoepidermal junction with destruction of anchoring fibrils.^{2,7,8,12,23,24} The third type involves multiple, non-scarring bullae on sun-exposed skin.² These types of bullae lesions reveal cleavages at the lamina lucida under histological observational studies.^2,23,24 Preventing infection is a primary focus of treating diabetic bullae. Podiatrists can help prevent infection by ensuring the patient is wearing properly fitting shoewear and socks to reduce friction at the bullae sites. The bullae heal spontaneously in two to five weeks but may recur in the same or new locations. What The Literature Reveals About Necrobiosis Lipoidica Diabeticorum Necrobiosis lipoidica diabeticorum. This cutaneous manifestation is described as a degenerative disease of collagen in the dermis and subcutaneous fat with an atrophic epidermis and granulomatous dermis.² The etiology has not clearly been described. Some suggested theories present a microangiopathic basis with neuropathy resulting in the degradation of collagen.^2,4,7,12 Cytokines from inflammatory cells may cause destruction of the collagenous matrix.^2,4 The majority of the lesions occur on the pretibial region of the lower legs. Necrobiosis lipoidica diabeticorum lesions occur in 0.3 to 0.7 percent of the diabetic population and have a greater prevalence among women. A few studies have correlated necrobiosis lipoidica diabeticorum and the microvascular effects of diabetic induced retinopathy and nephropathy.^2,4,7,12 The initial lesion is described as a well circumscribed erythematous plaque with a depressed, waxy telangiectatic center.^2,4,7,12 As time passes, granulomatous lesions evolve into a sclerotic stage of the dermis and subcutaneous fat.² While there is no standard therapy for this cutaneous manifestation, some anecdotal reports suggest that nonsteroidal agents or intralesional, systemic or topical corticosteriods may be helpful.² What About Perforating Dermatosis And Eruptive Xanthomas? Perforating dermatosis. One would see this manifestation in a majority of patients who have kidney failure associated with diabetes.^2,4,12 The associated itching and scratching accompanying perforating dermatosis is known as Kyrel’s disease or reactive perforating collagenosis.^2,4,7,12 These lesions are principally located on the extensor surfaces of the lower extremities and may occur on the face or trunk.^2,4,7,12 These papules are between 2 to 10 mm in diameter and often contain a keratotic plug. Histological studies reveal that these lesions have a hyperplastic epidermis surrounding a plug of degenerated material containing leuckocytes, collagen and nuclear debris.^2,7,25 Eruptive xanthomas. In diabetes, eruptive xanthomas are accompanied by hyperlipidemic and hyperglycemic states. The lesions are yellow, waxy papules surrounded by an erythematous rim. They usually occur on the extensor surfaces and the popliteal regions. Histologic studies of eruptive xanthomas will reveal lipid-laden histocytes and a mixed lymphoneutrophilic infiltrates in the dermis.² Key Insights On Tinea Pedis And Candida Infections Dermatophytic infections are particularly concerning among patients with diabetes because they may serve as a portal of entry for bacterial infections. Dermatophytic infections are generally restricted to nonliving, cornified layers of skin, hair or nails. The burning and pruritus symptoms of dermatophytic infections are due to the accumulation of their metabolic waste products. These symptoms may either be intense or patients may be asymptomatic. Dermatophytes release keratinases and other proteolytic enzymes that act upon the proteins present in keratinized structures skin, hair and nails. When treating patients with diabetes who have severe neurovascular complications, one should always evaluate these patients for intertriginous or interdigital infections caused by Trichophyton rubrum, Trichophyton mentagrophytes or Epidermophyton floccosum.⁴ Tinea pedis caused by Trichophyton mentagrophytes commonly starts in the third and fourth interdigital spaces.¹² The interspace web lesions are often macerated and have scaling borders and at times may be vesicular. Trichophyton rubrum produces scaling and thickening of the soles, often extending just beyond the plantar surface in a moccasin distribution. Tinea pedis may be complicated by secondary bacterial infection, cellulitis or lymphangitis. If chronic tinea pedis infections go untreated, they can spread to the toenails and destroy the nail plates. The treatment of interdigital tinea pedis depends on the severity of the disease. Whether one uses a cream or a gel, antifungal topical products can help dry interdigital maceration. Researchers have discussed topical products, classifications and the effectiveness of these agents in both tertiary and primary literature sources.^26-30 Candida infections commonly develop in older patients with diabetes mellitus and may be an early indicator of undiagnosed diabetes mellitus. Candida paronychia commonly involves the nail fold. Its symptoms include erythema, swelling, pain and loss of the cuticle. Extensive erythrasma occurs in obese patients with diabetes and is caused by the infectious agent Corynebacterium minutissimum. Common bacterial infections of the diabetic skin are caused by Staphylococcus aureus and B-hemolytic streptococci. The conditions these organisms cause include impetigo, folliculitis, furuncles, carbuncles, ecthymata, cellulitis and erysipelas.^4,7 Lower extremity erysipelas infections are often complicated by bullous lesions, leading to diabetic gangrene.^4,7,12 Understanding The Possible Consequences Of Untreated Onychomycosis In Patients With Diabetes Researchers have reported the prevalence of onychomycosis among diabetic patients to be as high as 35 percent.^3,31-33 One commonly sees onychomychosis in association with tinea pedis. It has an 80 percent prevalence rate among the elderly because of its strong age dependency. If onychomychosis is neglected in the patient with diabetes, it can contribute to severe consequences in the diabetic foot. Patients with diabetes who suffer from peripheral sensory neuropathy and impaired circulation are at a higher risk of developing complications from onychomycotic nails.³ Treatment options for onychomycosis are similar for patients with diabetes and those without the disease. There is a variety of treatment options available to treat onychomycosis. They include mechanical debridement, topical antifungal medications, oral antifungal agents and surgical intervention. One should exercise caution when considering surgical intervention in these patients due to the possible risk of secondary infections.³ How To Recognize Common Cutaneous Reactions To Diabetes Medications The incidence of allergic reactions to insulin varies from 5 to 10 percent.^4,7 Both local and systemic allergic reactions occur within the first month of therapy.¹² Historically, allergic reactions have been attributed to impurities found in both the beef and pork insulin preparations, the insulin molecule, and preservatives and additives like zinc.¹² The highly purified or recombinant insulin have reduced allergy prevalence to between 0.1 percent and 0.2 percent.^12,13 Cutaneous allergic reactions take the form of erythematous or uticarial pruritic nodules at the injection site. They may appear immediately, within 15 minutes to two hours, or be delayed with an onset of four hours or more after injection.¹² These reactions spontaneously resolve so treatment may be unnecessary. Podiatrists may be able to intervene at two points. First, they may observe the patient’s injection technique to ensure the injection itself is not intradermal in nature. Also, they may act as patient advocates and suggest to the prescribing physician the substitution of a more purified insulin as the treatment of choice. Mostly, children and obese women experience insulin-induced lipatropy or loss of fat at the site of injection. These atrophic plaques appear six to 24 months after starting injections. Both lipolytic components of insulin preparations or an immune complex mediated inflammatory process that causes the release of lysosomal enzymes have been implicated in the pathogenesis of insulin induced lipatrophy.^4,7,12 First generation sulfonylureas, such as chlorpropamide, are agents that have reportedly generated the majority of cutaneous reactions among patients with diabetes.^6,9,14 Of the patients who take a sulfonylurea, 1 to 5 percent develop a self-limiting maculopapular eruption type of cutaneous reaction with two months of starting therapy. One may also see morbilliform eruptions, generalized erythema or urticarial lesions.^4,7,12,34 Litt’s Drug Eruption Reference manual notes that using sulfonylureas can cause other reported cutaneous reactions including generalized erythema, urticaria, photosensitivity, lichenoid eruptions, erythema multiforme, exfoliative dermatitis and erythema nodosum.³⁴ The photosensitive reactions caused by sulfonylureas may be either photoallergic or phototoxic but photopatch tests are often negative.³⁴ The most frequently reported cutaneous reactions reported by Litt’s Drug Eruption Reference manual for glyburide included erythema, exanthems, photosensivity, pruritus and urticaria. The manufacturer states the incidence of rash or dermatitis in patients receiving metformin alone is similar to that with placebo, while the incidence of dermatological side effects in patients receiving both metformin and sulfonylurea antidiabetic agents is similar to the incidence of receiving an oral antidiabetic sulfonylurea alone.³⁴ Stevens-Johnson syndrome has been reported to occur in less than 1 percent of patients receiving repaglinide.³⁵ Final Words Early detection of skin manifestations of diabetes can help prevent potentially devastating complications. Educational intervention is critical. One should remind patients that bacterial and fungal infections of the skin are often associated with diabetes. Preventing these infections requires meticulous care of the patient’s lower extremities. Dr. Smith has a private practice in Ormond Beach, Fla.

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References 1. National Diabetes Fact Sheet: National estimates on diabetes. Available at: www.cdc.gov/diabetes/pubs/estimates.htm Accessed March 19,2003. 2. Chakrabarty A, Norman RA, and Phillips TJ. Cutaneous manifestations of diabetes. Wounds 2002; 14(8): 267-274. 3. Pollak RA. How to treat onychomycosis in diabetic patients. Podiatry Today 2003; 16(3):40-50. 4. Meurer M and Szeimies R. Diabetes mellitus and skin disease. Curr Probl Dermatol 1991; 20: 11-23. 5. Vowden P. Peripheral arterial disease. 1: Functional investigations. J Wound Care 1997; 6 (2): 77-78. 6. Vowden KR and Vowden P. Peripheral arterial disease. An update on epidemiology, pathology and aetilogy of vascular disease. J Wound Care 1996 5(1): 23-26. 7. Perez MI and Kohn SR. Cutaneous manifestation of diabetes mellitus. J Am Acad Dermatol 1994;30(4): 519-531. 8. Huntley AC. Cutaneous manifestation of diabetes mellitus. Dermatol Clin 1989; 7 (3):531-546, 9. LoGerfo FW, Coffman JD. Vascular and microvascular disease of the foot in diabetes: implications for foot care. N Engl J Med 1984;311 (25):1615-1619. 10. Greene RA, Scher RK. Nails changes associated with diabetes mellitus. J Am Acad Dermatol 1987; 16(5 pt 1): 1015-1020. 11. Kempers S, Katz HH, Wildnauer R, et al. An evaluation of the effect of an alpha hydroxy acid-blend skin cream in the cosmetic improvements of symptoms of moderate to severe xerosis, epidermolytic hyperkerotosis and ichthyosis. Cutis 1998; 61 (6): 347-350. 12. Ferringer T and Miller OF. Cutaneous manifestations of diabetes mellitus. Dermatol Clin 2002; 20(3): 483-492. 13. Paron NG and Lambert PW. Cutaneous manifestations of diabetes mellitus. Prim Care 2000; 27 (2): 371-383. 14. Romano G, Moretti G, Di Benedetto A et al. Skin lesions in diabetes mellitus: prevalence and clinical correlations. Diabetes Res Clin Pract 1998; 39 (2) 101-106. 15. Huntley AC and Walter RM. Quantitative determination of skin thickness in diabetes mellitus: relationship to disease parameters. J Med 1990; 21(5): 257-264. 16. Hanna W, Friesen D, Bombardier C et al. Pathologic feactures of diabetic thick skin. J Am Acad Dermatol 1987; 16 (3): 546-553. 17. Eaton PR. The collagen hydration hypothesis: a new paradigm for secondary complications of diabetes mellitus. J Chron Dis 1986; 39 (10): 763-766. 18. Huntley A and Drugge R. Diabetes in skin disease in The Electronic textbook of Dermatology http:/www.telemedicine.org/stamford.htm Accessed March 2003. 19. Aye M and Masson EA. Dermatological care of the diabetic foot. Am J Clin Dermatol 2003 3(7): 463-474. 20. Shemer A, Bergman R, Linn S et al. Diabetic dermopathy and internal complications in diabetes mellitus. Int J Dermatol 1998; 37(2): 113-115. 21. Bauer M, Levan NE. Diabetic dermangiopathy: a spectrum including pretibial pigmented pathches and necrobiosis diabeticorum. Br J Dermatol 1970; 83 (5): 528-535. 22. Binkley GW, Giraldo B, Stroughton RB. Diabetic dermopathy: a clinical study. Cutis 1967; 3(9): 955-958. 23. Bernstein JE, Medenica M, Soltani K, et al Bullous eruption of diabetes mellitus. Arch Dermatol 1979; 115 (3):324-325. 24.Toonstra J. Bullous diabeticorum. J Am Acad Dermatol 1985; 13 (5 pt 1): 799-805. 25. Zelger B, Hinter H, Aubock J et al. Acquired perforating dermatosis: Transepidermal elimination of DNA material and possible role of leukocytes in pathogenesis. Arch Dermatol 1991; 127 (5): 695-700. 26. Burnham TH, Wickersham, RM, Novak KK et al. Anti-infectives topical. In Drug Facts and Comparisons. St. Louis and Comparsions; 2003 1610-1619 27. Elewski B, Bergstresser PR, Hanifen J, et al. Long-term outcome of patients with interdigital tinea pedis treated with terbinafine or clotrimazole. J Am Acad Dermatol 1995; 32 (2 pt 1): 290-292 28. Bergstresser PR, Elewski B, Hanifin J et al. Topical terbinafine and clotrimazole interdigital tinea pedis: a multicenter comparison of cure and relapse rates with 1 and 4 week treatment regimen. J Am Acad Dermatol. 1993; 28 (4): 648-651 29. Shear NH, Einarson TR, Arikian SR et al. Pharmacoeconomic analysis of topical treatments for tinea infections. Int J Dermatol. 1998; 37 (1): 64-71. 30. Diehl KB. Topical antifungal agents: an update. Am Fam Physician 1996; 54 (5): 1687- 1692 31. Schlefman BS. Onychomycosis: a compendium of facts and clinical experience. J Foot Ankle Surg. 1999; 38 (4): 290-302. 32. Gupta AK, Konnikov N, MacDonald P et al. Prevalence and epidermiology of toenail onychomycosis in diabetic subjects: a multicenter survey. Br J Dermatol. 1998; 139 (4):665-671. 33. Gupta AK, Humke S. The prevalence and management of onychomycosis in diabetic patients. Eur J Dermatol 2000; 10 (5): 379-384. 34. Litt JZ. Physcian’s guide to drug eruption. New York: Parthenon Publishing; 1998. 95. 35. Burnham TH, Wickersham, RM, Novak KK et al. Antidiabetic agents. In Drug Facts and Comparisons. St. Louis and Comparsions; 2003 305-307.

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