A Guide To Cutaneous Manifestations Of Diabetes

      As the diabetic population continues to swell worldwide, there has also been an increased occurrence of various cutaneous manifestations associated with the disease. Researchers have reported a greater than 30 percent incidence of these disorders and they have been found in up to 70 percent of all patients with diabetes at some point during the course of their illness.1-5 Another problematic statistic for the diabetic population is the fact that 15 percent of all people with diabetes will experience at least one ulceration during their lifetime.6       Although those with type 1 diabetes are more highly associated with developing autoimmune type cutaneous lesions, non-insulin dependent diabetic patients can also be afflicted by these lesions.7,8 One common cause of these cutaneous lesions appears to be poor glycemic control. Other typical findings associated with uncontrolled diabetes that contribute to the various cutaneous manifestations include neuropathy, immunopathy, angiopathy and nephropathy among others. While insulin-dependent diabetic patients are more predisposed to these cutaneous lesions, patients with type 2 are at an increased risk to develop skin infections, which one may see in 50 percent of these patients.9,10       Accordingly, let us take a closer look at the more common diabetic cutaneous afflictions and their proposed etiologies. Diabetic ulcerations and various associated infections have been covered in depth in previous articles in this publication. Therefore, we will direct our focus toward the more autoimmune cutaneous presentations.

What The Research Reveals About Cutaneous Disorders In Patients With Diabetes

      There have been theories about an array of etiologies that may account for various diabetic cutaneous symptomatologies. However, alterations in metabolism and microangiopathy may help explain the predisposition for development.11 Microangiopathic changes are associated with abnormalities of local skin perfusion and the loss of capillary reserve.11 The failure of the microcirculatory system to meet the metabolic requirements of skin results in a variety of presentations. Further, it also serves as one of the main culprits in the development of diabetic foot ulcerations. The combination of small vessel disease, decreased large vessel run-off, neuropathy, susceptibility to infection and altered biomechanics all play a part in diabetic wound formation and cutaneous manifestations.11       Vascular endothelial cells are susceptible to hyperglycemic damage.12,13 Abnormalities in the aldose reductase pathway lead to an increase in sorbitol and other biochemical changes that directly contribute to endothelial damage.14,15 Hyperglycemic states of patients with poorly controlled diabetes also lead to glycylated end-products, which become deposited in the basement membrane in vascular endothelial cells.16 This process interferes with endothelial receptors and ultimately has negative effects on adhesions to the endothelium.6       Hyperglycemia also causes stress on antioxidants by creating a surplus of oxygen radicals. Excess radicals, which suppress nitric oxide production and release, contribute to the endothelial damage as well.17 Prolonged hyperglycemic states lead to activation of protein kinase C, which up-regulates several growth factors, leading to production of oxygen species and glycation end products.11 Although large vessel disease, which is common among those with diabetes, limits blood flow getting to the skin, it is the impairment in the capillary beds that impairs skin perfusion.18-20 Decreased microcirculation ultimately leads to tissue death due to the reduced supply of oxygen, nutrients and mediators that facilitate the repair process during injury. The tissue death results in local functional ischemia of the skin.21,22       Abnormalities in the venous system can also contribute significantly to the predisposition to develop lower extremity cutaneous manifestations. Visceral obesity can lead to increased venous pressure in the vena cava, which, in turn, creates venous pressure distally.19 Areas of increased venous pressure are at greater risk for skin breakdown secondary to metabolic derangements that lead to capillary convolution and destruction.23 The venous hypertension-induced edema is associated with increased capillary pressure. Heightened pressure in the capillaries causes oxygen tension to lower, increasing capillary leakage and decreasing the overall capillary reserve.24 The deleterious effects of underlying diabetic microangiopathy are compounded by increased lower extremity venous pressure. Treatment of venous stasis still involves various forms of compression therapy, lifestyle alterations and systemic control of hypertension.       Researchers have also shown that another predisposing factor for potential cutaneous involvement is the possibility of thicker skin among patients with diabetes, especially on the plantar surfaces of the feet.25 There may be increased thickening anywhere from 8 to 50 percent among people with diabetes as compared to non-diabetics and commonly has a shiny appearance.26 This occurrence is likely the result of glycylation of collagen bundles leading to an increase in cross-linking.27,28 As a result, the pathologic features of this phenomenon may also lead to limited joint mobility and contractures, which can put the integument in a more compromised position, secondary to abnormal biomechanics and pressure related to the increase in the epidermis and dermis.14,29-31       One may also note limited joint mobility in the diabetic population and this puts these patients at risk for additional cutaneous disruption. Typically, limited joint mobility presents as tightness and thickening of the skin and periarticular contraction of connective tissue. Although this problem afflicts the hands and fingers most commonly, it can affect the feet as well.30,31 It is associated with longstanding diabetes, poor glucose control and microangiopathy.30,31

What You Should Know About Necrobiosis Lipoidica

      Necrobiosis lipoidica is a fairly uncommon cutaneous disorder that has an incidence rate between 0.3 percent and 1.6 percent in patients with diabetes.8,32-34 This disorder is not exclusive to the diabetic population but over 90 percent of patients with necrobiosis lipodica have or will develop diabetes mellitus in their lifetime.4,35 The severity of cutaneous outbreaks does not correspond to the level of hyperglycemic control.36 Two-thirds of patients who get this cutaneous disorder are insulin-dependent. Generally, women in their 30s and 40s are more likely to develop necrobiosis lipoidica although the reason why is unclear.4       Lesions typically occur in the pre-tibial area. While 80 percent of these lesions arise here, one may see these lesions anywhere on the lower extremities.37 These lesions have been described as well circumscribed erythematous and violaceous papules that slowly enlarge and form a larger plaque where localized neuropathy tends to occur. The lesions range in size from a few millimeters to several centimeters and have sunken-in centers that are brown and yellow. Generally, the periphery of the lesion is raised and contains a reddish-blue hue.10 Lesions typically have prominent, crossing telangiectasias and ulcerate in a third of the documented cases. Typically, the lesions are bilateral in nature.7,10 Histologically, one will see epidermal atrophy and degenerative changes in collagen with granulomatous changes in the reticular dermis and fatty deposition in the papillary dermis.10,27       Treatment is conservative in nature as one would utilize topical or intralesional steroids to calm acute flares. When it comes to treating chronic lesions, clinicians should not use steroids because they may exacerbate the already present cutaneous atrophy. Ulcerations may become prominent and one would accordingly implement local wound care.5 There have also been solid, documented results in the removal of these lesions with excision followed by split-thickness skin grafting.38

How To Treat Diabetic Bullae

      Bullous diabeticorum, more commonly referred to as diabetic bullae, occurs in 0.5 percent of patients with diabetes.4 One generally sees these lesions in the adult diabetic population who have long-standing disease. The lesions are usually confined to the hands and feet.4,7 The lesions typically arise spontaneously with a sudden blister or bullae formation that can be up to 5 cm in diameter and contain serous fluid on a non-inflammatory base.7 The bullae are subepidermal lesions at the level of the lamina lucida.10,27,39 The blisters are painless and resolve themselves in two to four weeks.32       One should aim treatment at local wound care with bullae evacuation while keeping the roof of the lesion intact. It may be necessary to perform a biopsy to rule out other disorders such as bullous pemphigous and squamous cell carcinoma among others. Even though the disease course is self-remitting, it is still possible to prevent secondary infection by use of good local wound care and antibiotics when necessary.

What About Granuloma Annulare?

      Granuloma annulare occurs in 0.5 percent to 10 percent of those with diabetes and is thought to be associated with necrobiosis lipoidica.4 Generally, one would see this lesion type in insulin-dependent diabetic populations, especially with young adults or children.4,40 Women are affected more often than men. Often seen on the dorsum of the feet, especially in areas of previous trauma, these lesions present as a ring of multiple small flesh- to red-colored papules with occasionally associated pruritis.7 The size of a crop of lesions can range from 0.5 to 5 cm.41 Histologically, granuloma annulare appear very similar to necrobiosis lipoidica but differs primarily by the presence of abundant mucin deposits throughout the dermis.7       No treatment is necessary as these lesions spontaneously resolve with time and 40 percent to 50 percent resolve completely within two years of onset. However, these lesions do have a 40 percent reoccurrence rate.27 Patients troubled by the appearance of these lesions can benefit from intralesional corticosteroid injections.28

How To Detect And Treat Acanthosis Nigricans

      Acanthosis nigricans is another cutaneous manifestation one may see in the diabetic population but it is also associated with other endocrine disorders, and is a general marker for insulin resistance.42 The lesions are described as hyperpigmented plaques that clinicians may see on extensor surfaces and most commonly the posterior neck. They are mostly asymptomatic but can occasionally be painful.43       The pathogenesis of acanthosis nigricans is likely related to high levels of circulating insulin that cross-react and bind to receptors related in insulin-like growth factor on keratinocytes and dermal fibroblasts.44 An increase in the number of melanocytes accounts for the hyperpigmented skin changes.       Several medications have also been implicated in the development of acanthosis nigricans and include systemic glucocorticoids, nicotinic acid and exogenous estrogens.45 Treatment centers around lifestyle alteration, recognition and cessation of offending medications along with concomitant control of hyperglycemic states and the use of topical keratolytics.

Pertinent Tips On Diabetic Dermopathy

      Diabetic dermopathy, also called “shin spots,” is perhaps the most commonly encountered cutaneous manifestation. It reportedly affects 12.5 percent to 70 percent of all patients with diabetes, and is more common among older males.2,10       One typically sees these cutaneous reactions among diabetic patients with other end-organ symptoms like retinopathy, nephropathy, neuropathy and microangiopathy.4 The course of the disease starts off small. Typically, 0.5 to 1.0 cm flesh- or pink-colored lesions develop over the anterior tibial area and evolve into hyperpigmented brownish, macular lesions with associated fine scales.27 The lesions are usually well circumscribed, can be numerous and tend to occur bilaterally but with an asymmetrical distribution.29       The etiology is unclear but previous trauma or infection appears to be correlated with the onset of these lesions.10,46 Histological appearance shows epidermal atrophy with thickening of dermal blood vessels, along with associated hemorrhage and hemosiderin pigmentation.10,27 Lesions tend to slowly resolve spontaneously within one to two years and often leave behind hyperpigmented areas of cicatrix.

Key Insights On Other Skin Conditions

      Some other cutaneous manifestations include lichen planus. This manifestation occurs in 1.6 percent to 3.8 percent of patients with diabetes and more commonly in the insulin-dependent population.4 Lesions appear to be violaceous and macular-papular, and are often pruritic, occurring over flexor surfaces of the lower extremities.2 The goal of therapy to treat this problem centers around controlling pruritis, which expedites resolution. One can achieve this with antihistamines and topical corticosteroids.       Another cutaneous disorder is xanthoma, which occurs as a result of elevated circulating triglycerides, and is associated with uncontrolled diabetes.7 Xanthomas appear as dome-shaped papules or nodules with a yellowish center on an erythematous base. They most commonly occur on extensor surfaces.7 These lesions have a propensity to be pruritic and can be painful. Often, these lesions are the first signs and symptoms of undiagnosed diabetes and hypertriglyceridemia.4 They tend to resolve spontaneously and quickly. Treatment revolves around systemic management of hyperglycemia and cholesterol.

In Summary

      Diabetes mellitus has been associated with many cutaneous manifestations and several have a predilection for the lower extremities. Although many of these manifestations have been highly correlated with diabetes, an exact etiology remains unknown for several of these diseases. It is important to recognize that these cutaneous disorders may be the first indication of undiagnosed diabetes.       Diabetic ulcerations, tinea and bacterial infections all share common underlying pathophysiologic changes, including microangiopathy, neuropathy, nephropathy and alterations in metabolic functions, as is the case with the aforementioned cutaneous manifestations. Disruption of the microcirculation and the inability to support local tissues may result in the diverse array of cutaneous lesions that one may see in the diabetic population.       Many of these cutaneous disorders often resolve spontaneously but may ulcerate and compound the treatment protocol. Demonstrating an awareness of these disorders, facilitating control of systemic abnormalities and performing local wound care when needed are keys to management in these situations.       Dr. Wilkinson is a third-year year resident at the Yale/VA-Connecticut Healthcare System.       Dr. Palladino is the Director of Research of the North American Center for Limb Preservation. He is a Fellow of the American College of Foot and Ankle Surgeons.       Dr. Blume is an Assistant Clinical Professor of Surgery in the Department of Orthopaedics and Rehabilitation at Yale University School of Medicine. He is the Director of Limb Preservation at Yale-New Haven Hospital in New Haven, Ct. Dr. Blume is a Fellow of the American College of Foot and Ankle Surgeons.       Editor’s note: For related articles, see “How To Detect And Treat Granuloma Annulare” in the December 2004 issue or visit the archives at www.podiatrytoday.com.
 

References:

1. Braverman I, et al. Cutaneous manifestations of diabetes mellitus. Med Clin N Am; 55:1019-1029, 1971.
2. DiBenedetto A, et al. Skin lesions in diabetes mellitus: prevalence and clinical correlations. Diabetes Research and Clinical Practice; 39:101-106, 1998.
3. Hall SE. The skin in diabetes mellitus, in Pickup JC, Williams G (eds). Chronic complications of diabetes. Oxford, Blackwell Scientific Publications 250-259, 1994.
4. Jelinek JD. Skin disorders associated with diabetes mellitus, In Rifkin H, Pourte D, (eds): Ellenberg and Rifkin’s Diabetes Mellitus: Theory and Practice, New York, Elsevier, 838-849, 1990.
5. Paron NG, et al. Cutaneous manifestations of diabetes mellitus. Dermatol; 27(2):371-383, 2000.
6. Reiber GE, et al. Lower extremity foot ulcers and amputations in diabetics: Diabetes in America 2nd ed. Bethesda, MD. National Diabetes Data Comp. NIH, 1995, NIH publication, 409-429.
7. Perez MI, et al. Cutaneous manifestations of diabetes mellitus. J Am Acad Dermatol; 30:519-531, 1994.
8. Yosipovitch G, et al. The prevalence of cutaneous manifestations in insulin-dependent diabetes mellitus and the association with diabetic risk factors and microvascular complications. Diabetes Care; 21:506, 1998.
9. Gorbach SL, et al. Infectious Diseases. 2nd ed. Philadelphia. WB Sanders, 1998.
10. Sibbald RG, et al. Skin and diabetes. Endocrinol Metab Clin N Am; 25:463-472, 1996.
11. Ngo BT, et al. Manifestations of cutaneous diabetic microangiopathy. Am J Clin Dermatol; 6(4):225-237, 2005.
12. Nishikawa T, et al. The missing link: a single unifying mechanism for diabetic complications. Kidney Int; 77:S26-30, 2000.
13. Tooke JE, et al. Possible pathophysiological mechanisms for diabetic angiopathy in type 2 diabetics. J Diabetes Complications;14:197-200, 2000.
14. Chandra D, et al. Role of aldose reductase in TNF-alpha induced apoptosis of vascular endothelial cells. Chem Bio Interact; 143(144):605-612, 2003.
15. Gabbay KH, et al. Hyperglycemia, polyol mechanism and complications of diabetes mellitus. Ann Rev Med; 26:521-536, 1975.
16. Vlassara H, et al. Diabetes and advanced glycation end products. Intern Med; 251:87-101, 2002.
17. Giugliano D, et al. Oxidative stress and diabetic vascular complications. Diabetes Care; 19:257-267, 1996.
18. Akbari CM, et al. Diabetes and peripheral vascular disease. J Vasc Surg; 30:373-384, 1999.
19. London NJ, et al. ABC of arterial and venous disease: ulcerated lower limbs. BMJ; 320:1589-1591, 2000.
20. Rendell M, et al. Cutaneous blood flow and peripheral resistance in type 2 diabetes as compared tom intermittent claudication patients. Int J Angiology; 12:166-171, 2003.
21. McNeely MJ, et al. The independent contributions of diabetic neuropathy and vasculopathy in foot ulcerations: how great are the risks. Diabetes Care; 18:216-219, 1995.
22. Rayman G, et al. Impaired microvascular hyperemic response to minor skin trauma in type 1 diabetes. BMJ; 292:1295-1298, 1986.
23. Geschwandtner ME, et al. Microcircualtion in chronic venous insufficiency. Vasc Med; 6:169-179, 2001.
24. Steins A, et al. Venous leg ulcers and microcirculation. Clin Hemorheol Microcirc; 24:147-153, 2001.
25. Hanna W, et al. Pathologic features of diabetic thick skin. J Am Acad Dermatol; 16:546-553, 1987.
26. Fitzcharles MA, et al. Limitation of joint mobility (cheiroarthropathy) in adult non-insulin dependent diabetic patients. Am Rhem Dis; 43:251-257, 1984.
27. Freinkel RK. Diabetes mellitus. In Freedberg IM, Eisen AZ, Wolff K, et al (eds) Fitzpatrick’s Dermatology in General Medicine, ed.5, New York McGraw-Hill, 1969-1975, 1999.
28. Studer Em, et al. Precipitating factors and associated diseases in 84 patients with granuloma annulare: a retrospective study. Dematol; 193:364, 1996.
29. Huntley AC. The cutaneous manifestations of diabetes mellitus. J Am Acad Dermatol; 7:427-455, 1982.
30. Rosenbloom AL. Limited joint mobility in insulin-dependent childhood diabetes. Eur J Pediatr; 149:380-388, 1990.
31. Rosenbloom GE, et al. Limited joint mobility in childhood diabetes mellitus indicates risk for microvascular disease. N Eng J Med; 305:191-194, 1981.
32. Ahmed I, et al. Diabetes Mellitus. Clin Dermatol; 24:237-246, 2006.
33. Muller SA, et al. Dermatologic disorders associated with diabetes mellitus. Mayo Clinic Proc; 41:689-703, 1966.
34. Muller, SA, et al. Necrobiosis lipoidica diabeticorum: A clinical and pathological Investigation of 171 cases. Arch Dermatol; 93:272-281, 1966.
35. Shall L, et al. Necrobiosis lipoidica: the footprint not the footstep. Br J Deramtol 123: (supp 137)47, 1990.
36. Dandona P, et al. Glycosylated haemoglobin in patients with necrobiosis lipoidica and granuloma annulare. Clin Exp Dematol; 6:299, 1981.
37. Mann RJ, et al. Cutaneous anesthesia in necrobiosis lipoidica. Br J Dermatol; 110:323, 1984.
38. Nylen BO, et al. Surgical treatment of necrobiosis lipoidica. Acta Derm Venereol; 3:366-371, 1958.
39. Toonstra J. Bullosis diabeticorum: report of a case with review of the literature. Acad Dermatol; 13:799-805, 1982.
40. Muhlemann MF, et al. Localized granuloma annulare is associated with insulin-dependent diabetes mellitus. Br J Dermatol; 111:325-329, 1984.
41. Samlaska CP, et al. Generalized perforating granuloma annulare. J Am Acad Dermatol; 27:319, 1992.
42. Kahn CR, et al. The syndromes of insulin resistance and acanthosis nigricans. N Eng J Med; 294:739-749, 1976.
43. Hermanns LE, et al. Acanthosis nigricans associated with insulin resistance: Pathophysiology and management. Am J Clin Dermatol; 5:199-203, 2004.
44. Cruz Jr P, et al. Excess insulin binding to insulin-like growth factor receptors: proposed mechanism for acanthosis nigricans. J Invest Dermatol; 98:82S, 1992.
45. Schwartz RA. Acanthosis nigricans. J Am Acad Dermatol; 31:1, 1994.
46. Lithner F, et al. Cutaneous reactions of diabetics to local thermal trauma. Acta Med Scanda; 198:319, 1975.
Additional References
47. Garza-Elizonodo MA, et al. Joint contractures and scleroderma-like skin changes in the hands of insulin-dependent juvenile diabetics. J Rheum; 10:797-800, 1988.
48. Shemer A, et al. Diabetic dermopathy and internal complications in diabetes mellitus. Int J Dermatol; 37:113-117, 1998.
49. Knight L, et al. Growth of Candida albicans in saliva. Stimulation by glucose associated with antibiotics, corticosteroids and diabetes mellitus. J Inf Disease; 123:371-377, 1971.
50. Petzelbauer P, et al. Necrobiosis lipoidica: treatment with systemic corticosteroids. Br J Dermatol; 126:542, 1992.