- Email: [email protected]
Skin blood flow abnormalities in diabetic dermopathy
Skin blood flow abnormalities in diabetic dermopathy Alexandra Brugler, BS,a Shaun Thompson, BS,a Scott Turner, BS,a Binh Ngo, MD,b and Marc Rendell, MDa Omaha, Nebraska, and Los Angeles, California Background: Diabetic dermopathy is the most common specific cutaneous finding in diabetes. Objective: Using laser Doppler technology, we tested the hypothesis that diabetic dermopathy arises from abnormal local skin blood flow. Methods: We measured cutaneous blood flow in patients with type 1 diabetes without dermopathy and compared values with those in a control group of patients with type 1 diabetes without diabetic dermopathy and in a nondiabetic group. We measured at 3 separate sites on the pretibial area on the legs of each participant, at dermopathy lesions, and at a number of standard sites on the upper and lower extremities. Results: We studied 25 patients with diabetes and diabetic dermopathy, average age 51 6 2 years, mean duration of diabetes 28 6 3 years. In all, 58 patients with type 1 diabetes without diabetic dermopathy served as control patients, average age 41 6 2 years, mean duration of diabetes 23 6 2 years. There were 67 nondiabetic control subjects, average age 47 6 3 years. The patients with diabetic dermopathy showed a marked reduction in skin blood flow at 358C at normal-appearing skin areas on the pretibial surface of the legs (1.1 6 0.1 mL/min/100 g) compared with 1.7 6 0.1 mL/min/100 g (P = .01) in the type 1 diabetic control group and 2.1 6 0.3 mL/min/100 g (P \ .01) in the nondiabetic group. The dermopathy lesions themselves showed markedly higher blood flow: 2.5 6 0.3 mL/min/100 g. Limitations: Our diabetic dermopathy patients were somewhat older than the control type 1 diabetes subjects, but were of comparable age to the nondiabetic subjects. Conclusions: These results suggest that patients susceptible to diabetic dermopathy have a functional abnormality in blood flow leading to this scarring process. ( J Am Acad Dermatol 2011;65:559-63.) Key words: diabetic dermopathy; diabetic nephropathy; diabetic retinopathy; laser Doppler; skin blood flow; type 1 diabetes.
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iabetic dermopathy is the most common cutaneous finding in diabetes, occurring in as many as 40% of patients with diabetes older than 50 years.1-7 Diabetic dermopathy characteristically appears as round to oval atrophic hyperpigmented macules on the pretibial areas of the lower legs. The lesions are usually bilateral and have From the Department of Medicine, Creighton University School of Medicine, Omahaa; and the Department of Dermatology, University of Southern California Keck School of Medicine, Los Angeles.b Supported by Rose Salter Medical Research Foundation, where Dr Rendell is Medical Director. Conflicts of interest: None declared. Accepted for publication June 4, 2010. Reprint requests: Marc Rendell, MD, Department of Medicine, Creighton Diabetes Center, 601 North 30 St, Suite 6715, Omaha, NE 68131. E-mail: [email protected]. Published online May 2, 2011. 0190-9622/$36.00 ª 2010 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2010.06.010
an asymmetric distribution. There is no similar skin condition in patients without diabetes. The lesions are seen more frequently in patients with diabetes of long duration and with coexisting diabetic microvascular disease.8 In prior studies, we have demonstrated a disorder of skin blood flow in patients with diabetes and no evidence of cutaneous disease. Although skin blood flow at basal body temperature is not different from that in nondiabetic subjects, there is a 40% to 50% reduction of heat-stimulated flow in patients with diabetes compared with the nondiabetic control population.9 This impairment affects patients with both type 1 and type 2 diabetes and presumably reflects a diabetic cutaneous microangiopathy.10,11 In a previous study, we used laser Doppler to determine if the skin lesions of diabetic dermopathy exhibited decreased blood flow, consistent with the hypothesis that these were ischemic areas resulting from diabetic microangiopathy. We found that diabetic dermopathy lesions actually had 559
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much higher blood flow than normal-appearing Bonner and Nossal.15 A low-power solid-state laser reference skin sites, similar to increased flow values diode provides the coherent light source that is in scars. We concluded that diabetic dermopathy delivered through a fiber optic line to a probe affixed lesions are nonischemic and represent a scarring to the skin with an adhesive ring. Two separate fiber process.12 optic lines gather the photons from the skin surface It is still possible that diabetic dermopathy lesions, and return them to a photodetector that converts although not ischemic themselves, may be related to them to a DC electrical signal related to the level of cutaneous diabetic microanscatter from stationary tissue giopathy. Conceivably, local and an additional small AC CAPSULE SUMMARY ischemia may predispose to signal generated by Dopplerthe scarring that these lesions shifted photons. The AC:DC Diabetic dermopathy is the most represent. To assess this posratio is converted to the avercommon skin disorder seen in patients sibility, we measured skin age number of Doppler shifts with diabetes. blood flow in a group of per photon. That number is patients with type 1 diabetes We measured skin blood flow on the proportional to the blood with diabetic dermopathy lepretibial surface of the legs, the typical volume. A signal-processing sions and a control group of site of diabetic dermopathy. algorithm converts a time dopatients with type 1 diabetes main autocorrelation to a freWe found significantly lower skin blood without dermopathy. We also quency domain that gives a flow on normal-appearing skin on the included a second control mean frequency proporpretibial surface of the legs of patients group of nondiabetic subtional to blood velocity. with diabetic dermopathy than in jects. We focused on the preBlood flow is the product matched control patients without this tibial surface of the legs, of linearized volume and vecondition. where these lesions typically locity. A calibration factor of We conclude that decreased cutaneous occur, comparing flow values 6 mL/100 ge1/mine1/100 Hz perfusion may contribute to the at unaffected skin sites in the has been derived on the basis development of diabetic dermopathy. diabetic dermopathy group of theoretical calculations to and in the two control popuconvert the laser Doppler lations. We standardized local skin temperature at flow parameter to conventional blood flow units15 358C to eliminate variation among the patient and has been verified in numerous tissues using groups. In addition, we also measured blood several reference techniques.16-21 flow at a maximal skin temperature of 448C. The Doppler fiber laser optic probes are inserted into a 19-mm diameter thermal head attached to a METHODS solid-state temperature controller. The temperature Patient selection was controlled in the range of 60.58C of set point. The We included male and female patients with type probe was placed so that the fiber optic ends were not 1 diabetes and evident diabetic dermopathy and a directly over a vein or hair follicle. Mean flow was control group of patients with type 1 diabetes without measured using a 5-second averaging time to encomdiabetic dermopathy, matched for age and duration pass cardiac pulsatile activity. of diabetes. We also recruited a control population of We measured flow directly on lesions of diabetic age-matched nondiabetic individuals. Informed dermopathy. We also obtained measurements at consent was obtained from each participant after nearby uninvolved sites on the pretibial surface of the nature of all procedures and the protection of the legs. We selected 3 visibly normal-appearing skin confidentiality had been fully explained. All patients sites on the lower aspect of the leg spaced at least 5 with diabetes were evaluated for the presence of cm from each other and no closer than 4 cm from the diabetes-associated complications. Microalbumin nearest dermopathy lesions. In the control groups, levels were determined in the urine. The existence we selected normal-appearing sites spaced no closer of diabetic neuropathy was established by assessing than 5 cm from each other. As additional reference symptoms and examining each patient for thermal, points, we also performed readings at the following light touch, vibratory, and pinprick sensation.13,14 locations typically not susceptible to diabetic dermopathy: (1) the plantar surface of the tip of the index finger (finger pulp); (2) the back surface of the Skin blood flow measurements distal phalange of the index finger, immediately We used a laser Doppler device (Vasamedic proximal to the nail bed (finger dorsum); (3) the model 403B, Vasamedics Inc, St Paul, MN) that was plantar surface of the tip of the great toe (toe pulp); designed based on the original theoretical model of d
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Table I. Clinical characteristics of the 3 participant groups
No. Age, y Duration of diabetes, y HbA1c No. with microalbuminuria No. with retinopathy No. with neuropathy
Nondiabetic
Diabetic with diabetic dermopathy
20 F/47 M 47 6 3 — — — — —
6 F/19 M 51 6 2* 28 6 3 7.5 6 0.3% 8 12 18
Diabetic without diabetic dermopathy
31 41 23 8.1
F/27 M 62 62 6 0.2% 6 17 13
F, Female; HbA1c, Hemoglobin A1c; M, male. *P \ .01 comparing diabetic dermopathy group with type 1 diabetic control group and nondiabetic control group.
(4) the extensor surface of the distal phalange of the great toe, immediately proximal to the nail bed (toe dorsum); (5) the pretibial surface of the leg immediately below the patella (knee); and (6) the back surface of the ankle, between the medial and lateral malleoli (ankle). The finger and toe pulps have a high density of arteriovenous anastomoses with a low resistance and high flow.22 The knee and ankle have a primarily nutritive capillary perfusion with high resistance and low flow.23 The back surfaces of the finger and toe have a relatively high, primarily nutritive capillary perfusion. Statistical analysis Comparisons were carried out by standard analysis of variance techniques. All results are presented as mean 6 SEM.
RESULTS Our study population consisted of 25 patients with type 1 diabetes and diabetic dermopathy, a control group of 58 patients with type 1 diabetes without diabetic dermopathy, and 67 nondiabetic control subjects. The characteristics of the 3 contrast groups are presented in Table I. The patients with diabetic dermopathy were older at an average age of 51 6 2 years than the control patients with type 1 diabetes whose average age was 41 6 2 years (P \ .01). As expected, the patients with diabetic dermopathy had a higher frequency of microalbuminuria, retinopathy, and neuropathy than the control patients with type 1 diabetes. As compared with both the nondiabetic group and the type 1 diabetic control group, the diabetic dermopathy group showed a marked reduction in skin blood flow at 358C at each of the 3 normalappearing skin areas on the pretibial surface of the legs (Table II). Flow in the diabetic dermopathy lesions themselves was significantly higher than at the normal-appearing skin sites in these patients (Table II).
Over all 3 of the normal-appearing test skin sites combined, mean skin blood flow in the diabetic dermopathy group was 1.1 6 0.1 mL/min/100 g at 358C compared with 1.7 6 0.1 mL/min/100 g in the patients with type 1 diabetes without dermopathy and 2.1 6 0.2 mL/min/100 g in the nondiabetic control group (P \ .01 comparing the diabetic dermopathy group with the type 1 diabetic control group and the nondiabetic group). At 448C, mean skin blood flow in the diabetic dermopathy group was 9.8 6 0.8 mL/min/100 g compared with 12.0 6 0.8 mL/min/100 g in the type 1 diabetic without dermopathy group (P \.06) and 13.1 6 1.3 mL/min/ 100 g in the nondiabetic control group (P \.05). We also measured skin blood flow at a number of standard sites (Table III). In addition to having lower blood flow at the normal-appearing skin sites on the pretibial surface of the leg, the diabetic dermopathy group also showed lower blood flow at 358C at the knee and at the ankle. Skin blood flow at 448C was reduced at the toe dorsum in both patients with diabetic dermopathy and control patients with type 1 diabetes as compared with patients without diabetes (Table III). Heat-stimulated blood flow was also reduced at the knee in both diabetic groups. There were no differences among the 3 groups at the two finger sites.
DISCUSSION In previous studies of diabetic dermopathy, we demonstrated higher blood flow in these lesions than in surrounding uninvolved areas. The lesions appear to be caused by a scarring process resulting from defective wound healing on the pretibial surface of the legs. In the current study, we have confirmed our prior finding of increased blood flow in dermopathy lesions, but have now shown that skin blood flow is reduced in nonaffected pretibial skin areas in patients with diabetic dermopathy. This reduction is apparent not only in comparison with a nondiabetic group but also to a control
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Table II. Skin blood flow at 3 normal-appearing skin sites in patients with diabetic dermopathy, control patients with type 1 diabetes without dermopathy, and patients without diabetes Normal-appearing site 1 358C
448C
Normal-appearing site 2 358C
448C
Normal-appearing site 3 358C
448C
Diabetic dermopathy sites 358C
448C
Type I diabetic control 1.8 6 0.2 11.9 6 1.5 1.8 6 0.3 11.9 6 1.6 1.5 6 0.2 12.2 6 1.2 — — Diabetic dermopathy 1.1 6 0.1* 10.6 6 1.6 1.1 6 0.1* 8.8 6 0.8 1.0 6 0.1* 10.2 6 1.5 2.5 6 0.3y 16.1 6 1.7y Nondiabetic 2.1 6 0.3 15.9 6 3.0 2.3 6 0.5 10.0 6 1.4 1.9 6 0.3 13.6 6 2.0 — — Flow is given in mL/min/100 g and reported as mean 6 SEM. *P \ .01 comparing diabetic dermopathy group with control type 1 diabetic group and nondiabetic control group. y P \ .01 comparing values at diabetic dermopathy sites with uninvolved skin areas in patients with diabetic dermopathy.
Table III. Skin blood flow at reference sites in the 3 groups Type 1 diabetic control
Finger pulp 358C 448C Finger dorsum 358C 448C Toe pulp 358C 448C Toe dorsum 358C 448C Knee 358C 448C Ankle 358C 448C
Diabetic dermopathy
Nondiabetic
40.0 6 2.8 87.0 6 4.9
34.5 6 4.2 85.0 6 6.0
39.8 6 3.3 84.2 6 3.5
13.5 6 1.7 41.9 6 4.4
10.0 6 2.5 37.0 6 5.0
10.1 6 1.3 36.7 6 2.9
17.8 6 2.5 59.4 6 4.2
14.8 6 2.6 48.6 6 5.3
14.2 6 2.1 66.2 6 4.4
3.7 6 0.6 15.1 6 1.6*
2.8 6 0.4 12.5 6 1.5y
3.4 6 0.5 22.4 6 2.5
2.4 6 0.3 14.5 6 1.2*
1.5 6 0.2z 12.3 6 1.2y
1.6 6 0.2 18.9 6 1.7
2.4 6 0.3 13.0 6 1.4
1.4 6 0.1§ 12.4 6 1.8
3.1 6 0.3 14.4 6 2.0
*P \ .05 compared with nondiabetic control group. y P \ .01 compared with nondiabetic control group. z P \ .01 comparing values in diabetic dermopathy group with type 1 diabetic control group. § P \ .01 comparing values in diabetic dermopathy group with both type 1 diabetic control group and nondiabetic group.
group of patients with type 1 diabetes and no evidence of diabetic dermopathy. This decrease in change to blood flow in normal appearing skin sites is clearly demonstrated at 358C, but is also present with maximal skin heating to 448C. Skin sites on the digits of the fingers and toes do not show such differences in skin blood flow, suggesting that there is a functional abnormality at the usual location of dermopathy lesions on the pretibial surface of the legs. The cause of this blood flow abnormality is not clearly apparent. Our patients with diabetic dermopathy had a higher frequency of diabetes-associated complications including retinopathy, microalbuminuria, and neuropathy than the control subjects with
type 1 diabetes. In particular, diabetic neuropathy was present in more than two thirds of the patients with dermopathy but less than 25% of the control diabetic group. It is conceivable that both diabetic microangiopathy and diabetic neuropathy contribute to the functional abnormality in blood flow. Diabetic neuropathy could alter arteriovenous shunting in skin capillaries leading to decreased local skin blood flow. The fact that diabetic dermopathy occurs primarily at the pretibial surface of the legs, an area with nutritive skin flow, rather than at sites endowed with high-density arteriovenous shunt microvessels, tends to argue against this possibility. It is also true that our patients with diabetic dermopathy were older at an average age of 51 years than the control subjects with type 1 diabetes whose average age was 41 years. However, we do not believe that this age difference accounts for the markedly lower blood flow observed in the patients with diabetic dermopathy because in a previous study of the effect of aging on skin blood flow we demonstrated minimal differences in skin blood flow at 358C, comparing volunteers of an average age of 29 years with volunteers of an average age of 76 years.24 Although diabetic dermopathy lesions themselves have increased blood flow, our current findings argue that the scarring of diabetic dermopathy is related to defective skin perfusion. Adequate skin blood flow is essential for proper wound healing.25-27 The pretibial surface of the leg is subject to recurrent minor traumatic events. Other investigators have documented that blood flow is increased in hypertrophic but not atrophic scars.28-31 Studies of burn wounds suggest that wounds that heal rapidly without scarring have higher initial perfusion than those with slow healing.32-34 It is therefore plausible that the decreased blood flow we have demonstrated on the pretibial leg surface predisposes patients with diabetes to inadequate wound healing resulting in formation of the scarring lesions of diabetic dermopathy. Although our results appear to refute the hypothesis that diabetic dermopathy represents local ischemia, it is still plausible that decreased skin blood
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flow leads to the development of diabetic dermopathy. It is possible that an active cutaneous flow is required for healing to proceed with minimal scar formation. A pronounced hyperemic response occurs early in the process of wound healing.25-27 Perhaps skin perfusion in patients with diabetes may be insufficient to heal wounds without scarring. Even minor trauma may lead to scar formation in these patients. This could be the origin of the lesions of diabetic dermopathy. Further studies must focus on this possibility. It remains to be understood why certain patients with type 1 diabetes have lower skin blood flow at the pretibial surface of the legs whereas other patients with type 1 diabetes have normal skin perfusion. We do not know the natural progression of skin blood flow reduction that may lead to an increased scar response resulting in diabetic dermopathy lesions. It would be of interest to carry out long-term longitudinal studies to see if skin blood flow measurement might have predictive value in indicating which patients are susceptible to dermopathy lesions. Finally, if skin blood flow reduction is causal in producing diabetic dermopathy, it may be possible to prevent or treat the process by finding means of increasing local skin perfusion. REFERENCES 1. Melin H. An atrophic circumscribed skin lesion in the lower extremities of diabetics. Acta Med Scand 1964;176(Suppl):1-75. 2. Murphy RA. Skin lesions in diabetic patients: the ‘‘spotted leg’’ syndrome. Lahey Clin Found Bull 1965;14:10-4. 3. Binkley GW, Giraldo B, Stoughton RB. Diabetic dermopathy: a clinical study. Cutis 1967;3:955-8. 4. Danowski TX, Sabeh G, Sarver ME, Shelkrot J, Fisher ER. Shin spots and diabetes mellitus. Am J Med Sci 1966;251:570-5. 5. Bauer M, Levan NE. Diabetic dermangiopathy: a spectrum including pretibial pigmented patches and necrobiosis lipoidica diabeticorum. Br J Dermatol 1970;83:528-35. 6. Huntley AC. Cutaneous manifestations of diabetes mellitus. Dermatol Clin 1989;7:531-46. 7. Jelinek JE. Cutaneous manifestations of diabetes mellitus. Int J Dermatol 1994;33:605-17. 8. Shemer A, Begman R, Linn S, Kantor Y, Friedman-Birnbaum RL. Diabetic dermopathy and internal complications in diabetes mellitus. Int J Dermatol 1998;37:113-5. 9. Rendell M, Bergman T, O’Donnell G, Drobny E, Borgos J, Bonner RF. Microvascular blood flow, volume, and velocity measured by laser Doppler techniques in insulin dependent diabetes. Diabetes 1989;38:819-24. 10. Rendell M, Bamisedun O. Diabetic cutaneous microangiopathy. Am J Med 1992;93:611-8. 11. Rendell M, Saxena S, Shah D. Cutaneous blood flow and peripheral resistance in type II diabetes as compared to intermittent claudication patients. Int J Angiol 2003;12:166-71. 12. Wigington G, Ngo B, Rendell M. Skin blood flow in diabetic dermopathy. Arch Dermatol 2004;140:1248-50. 13. Rendell MS, Dovgan DJ, Bergman TF, O’Donnell GP, Drobny EP, Katims JJ. Mapping diabetic sensory neuropathy by current perception threshold testing. Diabetes Care 1989;12:636-40.
14. Rendell M, Consensus Development Group. Proceedings of a consensus development conference on standardized measures in diabetic neuropathy. Diabetes Care 1992;15(Suppl): 1080-107. 15. Bonner R, Nossal R. Model for laser Doppler measurements of blood flow in tissue. Appl Opt 1981;20:2097-107. 16. Nitzan M, Fairs SLE, Roberts VC. Simultaneous measurement of skin blood flow by the transient thermal-clearance method and laser Doppler flowmetry. Med Biol Eng Comput 1988;6: 407-10. 17. Saumet JL, Dittmar A, Leftheriotis G. Non-invasive measurement of skin blood flow, comparison between plethysmography, laser Doppler flowmeter and heat thermal clearance method. Int J Microcirc Clin Exp 1986;5:73-83. 18. Chung RS, Bruch D, Dearlove J. Endoscopic measurement of gastric mucosal flow by laser Doppler velocimetry: effect of chronic esophageal variceal sclerosis. Am Surg 1988;4:116-20. 19. Engelhart B, Meret M, Kristensen JK. Evaluation of cutaneous blood flow responses by 133-Xenon washout and a laser Doppler flowmeter. J Invest Dermatol 1983;80:12-5. 20. Kvietys PR, Shepherd AP, Granger DN. Laser-Doppler, H2 clearance, and microsphere estimates of mucosal blood flow. Am J Physiol 1985;249:G221-7. 21. Winsor T, Haumschild DJ, Winsor DW, Wang W, Luong TN. Clinical application of laser Doppler flowmetry for measurement of cutaneous circulation in health and disease. Angiology 1987;38:727-36. 22. Popoff NW. The digital vascular system. Arch Pathol 1934;18: 295-330. 23. Rowell LB. Reflex control of the cutaneous vasculature. J Invest Dermatol 1977;69:154-66. 24. Evans E, Rendell M, Bartek J, Connor S, Bamisedun O, Dovgan D, et al. Thermally induced cutaneous vasodilatation in aging. J Gerontol 1993;48:M53-7. 25. Rendell MS, Milliken BK, Finnegan MF, Finney DE, Healy JC. The skin blood flow response in wound healing. Microvasc Res 1997;53:222-34. 26. Rendell MS, Milliken BK, Finnegan MF, Finney DE, Healy JC, Bonner RF. A comparison of the microvascular response in the healing wound in the spontaneously hypertensive and nonhypertensive rat. Int J Surg Invest 2000;2:17-25. 27. Rendell M, Johnson ML, Smith D, Finney D, Capp C, Lammers R, et al. The skin blood flow response in the rat model of wound healing: expression of vasoactive factors. J Surg Res 2002;107:18-26. 28. Timar-Banu O, Beauregard H, Tousignant J, Lassonde M, Harris P, Viau G, et al. Development of noninvasive and quantitative methodologies for the assessment of chronic ulcers and scars in humans. Wound Repair Regen 2001;9:123-32. 29. Musgrave MA, Umraw N, Fish JS, Gomez M, Cartotto RC. The effect of silicone gel sheets on perfusion of hypertrophic burn scars. J Burn Care Rehabil 2002;23:208-14. 30. Ehrlich HP, Kelley SF. Hypertrophic scar: an interruption in the remodeling of repairea laser Doppler blood flow study. Plast Reconstr Surg 1992;90:993-8. 31. Clark JA, Leung KS, Cheng JC, Leung PC. The hypertrophic scar and microcirculation properties. Burns 1996;22:447-50. 32. Lithner F. Cutaneous reactions of the extremities of diabetics to local thermal trauma. Acta Med Scand 1975;198:319-25. 33. Svedman P, Svedman C, Njalsson T. Epithelialization and blood flow in suction blister wounds on healthy volunteers. J Invest Surg 1991;4:175-89. 34. Atiles L, Mileski W, Purdue G, Hunt J, Baxter C. Laser Doppler flowmetry in burn wounds. J Burn Care Rehabil 1995;16: 388-93.
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iabetic dermopathy is the most common cutaneous finding in diabetes, occurring in as many as 40% of patients with diabetes older than 50 years.1-7 Diabetic dermopathy characteristically appears as round to oval atrophic hyperpigmented macules on the pretibial areas of the lower legs. The lesions are usually bilateral and have From the Department of Medicine, Creighton University School of Medicine, Omahaa; and the Department of Dermatology, University of Southern California Keck School of Medicine, Los Angeles.b Supported by Rose Salter Medical Research Foundation, where Dr Rendell is Medical Director. Conflicts of interest: None declared. Accepted for publication June 4, 2010. Reprint requests: Marc Rendell, MD, Department of Medicine, Creighton Diabetes Center, 601 North 30 St, Suite 6715, Omaha, NE 68131. E-mail: [email protected]. Published online May 2, 2011. 0190-9622/$36.00 ª 2010 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2010.06.010
an asymmetric distribution. There is no similar skin condition in patients without diabetes. The lesions are seen more frequently in patients with diabetes of long duration and with coexisting diabetic microvascular disease.8 In prior studies, we have demonstrated a disorder of skin blood flow in patients with diabetes and no evidence of cutaneous disease. Although skin blood flow at basal body temperature is not different from that in nondiabetic subjects, there is a 40% to 50% reduction of heat-stimulated flow in patients with diabetes compared with the nondiabetic control population.9 This impairment affects patients with both type 1 and type 2 diabetes and presumably reflects a diabetic cutaneous microangiopathy.10,11 In a previous study, we used laser Doppler to determine if the skin lesions of diabetic dermopathy exhibited decreased blood flow, consistent with the hypothesis that these were ischemic areas resulting from diabetic microangiopathy. We found that diabetic dermopathy lesions actually had 559
560 Brugler et al
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much higher blood flow than normal-appearing Bonner and Nossal.15 A low-power solid-state laser reference skin sites, similar to increased flow values diode provides the coherent light source that is in scars. We concluded that diabetic dermopathy delivered through a fiber optic line to a probe affixed lesions are nonischemic and represent a scarring to the skin with an adhesive ring. Two separate fiber process.12 optic lines gather the photons from the skin surface It is still possible that diabetic dermopathy lesions, and return them to a photodetector that converts although not ischemic themselves, may be related to them to a DC electrical signal related to the level of cutaneous diabetic microanscatter from stationary tissue giopathy. Conceivably, local and an additional small AC CAPSULE SUMMARY ischemia may predispose to signal generated by Dopplerthe scarring that these lesions shifted photons. The AC:DC Diabetic dermopathy is the most represent. To assess this posratio is converted to the avercommon skin disorder seen in patients sibility, we measured skin age number of Doppler shifts with diabetes. blood flow in a group of per photon. That number is patients with type 1 diabetes We measured skin blood flow on the proportional to the blood with diabetic dermopathy lepretibial surface of the legs, the typical volume. A signal-processing sions and a control group of site of diabetic dermopathy. algorithm converts a time dopatients with type 1 diabetes main autocorrelation to a freWe found significantly lower skin blood without dermopathy. We also quency domain that gives a flow on normal-appearing skin on the included a second control mean frequency proporpretibial surface of the legs of patients group of nondiabetic subtional to blood velocity. with diabetic dermopathy than in jects. We focused on the preBlood flow is the product matched control patients without this tibial surface of the legs, of linearized volume and vecondition. where these lesions typically locity. A calibration factor of We conclude that decreased cutaneous occur, comparing flow values 6 mL/100 ge1/mine1/100 Hz perfusion may contribute to the at unaffected skin sites in the has been derived on the basis development of diabetic dermopathy. diabetic dermopathy group of theoretical calculations to and in the two control popuconvert the laser Doppler lations. We standardized local skin temperature at flow parameter to conventional blood flow units15 358C to eliminate variation among the patient and has been verified in numerous tissues using groups. In addition, we also measured blood several reference techniques.16-21 flow at a maximal skin temperature of 448C. The Doppler fiber laser optic probes are inserted into a 19-mm diameter thermal head attached to a METHODS solid-state temperature controller. The temperature Patient selection was controlled in the range of 60.58C of set point. The We included male and female patients with type probe was placed so that the fiber optic ends were not 1 diabetes and evident diabetic dermopathy and a directly over a vein or hair follicle. Mean flow was control group of patients with type 1 diabetes without measured using a 5-second averaging time to encomdiabetic dermopathy, matched for age and duration pass cardiac pulsatile activity. of diabetes. We also recruited a control population of We measured flow directly on lesions of diabetic age-matched nondiabetic individuals. Informed dermopathy. We also obtained measurements at consent was obtained from each participant after nearby uninvolved sites on the pretibial surface of the nature of all procedures and the protection of the legs. We selected 3 visibly normal-appearing skin confidentiality had been fully explained. All patients sites on the lower aspect of the leg spaced at least 5 with diabetes were evaluated for the presence of cm from each other and no closer than 4 cm from the diabetes-associated complications. Microalbumin nearest dermopathy lesions. In the control groups, levels were determined in the urine. The existence we selected normal-appearing sites spaced no closer of diabetic neuropathy was established by assessing than 5 cm from each other. As additional reference symptoms and examining each patient for thermal, points, we also performed readings at the following light touch, vibratory, and pinprick sensation.13,14 locations typically not susceptible to diabetic dermopathy: (1) the plantar surface of the tip of the index finger (finger pulp); (2) the back surface of the Skin blood flow measurements distal phalange of the index finger, immediately We used a laser Doppler device (Vasamedic proximal to the nail bed (finger dorsum); (3) the model 403B, Vasamedics Inc, St Paul, MN) that was plantar surface of the tip of the great toe (toe pulp); designed based on the original theoretical model of d
d
d
d
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Table I. Clinical characteristics of the 3 participant groups
No. Age, y Duration of diabetes, y HbA1c No. with microalbuminuria No. with retinopathy No. with neuropathy
Nondiabetic
Diabetic with diabetic dermopathy
20 F/47 M 47 6 3 — — — — —
6 F/19 M 51 6 2* 28 6 3 7.5 6 0.3% 8 12 18
Diabetic without diabetic dermopathy
31 41 23 8.1
F/27 M 62 62 6 0.2% 6 17 13
F, Female; HbA1c, Hemoglobin A1c; M, male. *P \ .01 comparing diabetic dermopathy group with type 1 diabetic control group and nondiabetic control group.
(4) the extensor surface of the distal phalange of the great toe, immediately proximal to the nail bed (toe dorsum); (5) the pretibial surface of the leg immediately below the patella (knee); and (6) the back surface of the ankle, between the medial and lateral malleoli (ankle). The finger and toe pulps have a high density of arteriovenous anastomoses with a low resistance and high flow.22 The knee and ankle have a primarily nutritive capillary perfusion with high resistance and low flow.23 The back surfaces of the finger and toe have a relatively high, primarily nutritive capillary perfusion. Statistical analysis Comparisons were carried out by standard analysis of variance techniques. All results are presented as mean 6 SEM.
RESULTS Our study population consisted of 25 patients with type 1 diabetes and diabetic dermopathy, a control group of 58 patients with type 1 diabetes without diabetic dermopathy, and 67 nondiabetic control subjects. The characteristics of the 3 contrast groups are presented in Table I. The patients with diabetic dermopathy were older at an average age of 51 6 2 years than the control patients with type 1 diabetes whose average age was 41 6 2 years (P \ .01). As expected, the patients with diabetic dermopathy had a higher frequency of microalbuminuria, retinopathy, and neuropathy than the control patients with type 1 diabetes. As compared with both the nondiabetic group and the type 1 diabetic control group, the diabetic dermopathy group showed a marked reduction in skin blood flow at 358C at each of the 3 normalappearing skin areas on the pretibial surface of the legs (Table II). Flow in the diabetic dermopathy lesions themselves was significantly higher than at the normal-appearing skin sites in these patients (Table II).
Over all 3 of the normal-appearing test skin sites combined, mean skin blood flow in the diabetic dermopathy group was 1.1 6 0.1 mL/min/100 g at 358C compared with 1.7 6 0.1 mL/min/100 g in the patients with type 1 diabetes without dermopathy and 2.1 6 0.2 mL/min/100 g in the nondiabetic control group (P \ .01 comparing the diabetic dermopathy group with the type 1 diabetic control group and the nondiabetic group). At 448C, mean skin blood flow in the diabetic dermopathy group was 9.8 6 0.8 mL/min/100 g compared with 12.0 6 0.8 mL/min/100 g in the type 1 diabetic without dermopathy group (P \.06) and 13.1 6 1.3 mL/min/ 100 g in the nondiabetic control group (P \.05). We also measured skin blood flow at a number of standard sites (Table III). In addition to having lower blood flow at the normal-appearing skin sites on the pretibial surface of the leg, the diabetic dermopathy group also showed lower blood flow at 358C at the knee and at the ankle. Skin blood flow at 448C was reduced at the toe dorsum in both patients with diabetic dermopathy and control patients with type 1 diabetes as compared with patients without diabetes (Table III). Heat-stimulated blood flow was also reduced at the knee in both diabetic groups. There were no differences among the 3 groups at the two finger sites.
DISCUSSION In previous studies of diabetic dermopathy, we demonstrated higher blood flow in these lesions than in surrounding uninvolved areas. The lesions appear to be caused by a scarring process resulting from defective wound healing on the pretibial surface of the legs. In the current study, we have confirmed our prior finding of increased blood flow in dermopathy lesions, but have now shown that skin blood flow is reduced in nonaffected pretibial skin areas in patients with diabetic dermopathy. This reduction is apparent not only in comparison with a nondiabetic group but also to a control
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Table II. Skin blood flow at 3 normal-appearing skin sites in patients with diabetic dermopathy, control patients with type 1 diabetes without dermopathy, and patients without diabetes Normal-appearing site 1 358C
448C
Normal-appearing site 2 358C
448C
Normal-appearing site 3 358C
448C
Diabetic dermopathy sites 358C
448C
Type I diabetic control 1.8 6 0.2 11.9 6 1.5 1.8 6 0.3 11.9 6 1.6 1.5 6 0.2 12.2 6 1.2 — — Diabetic dermopathy 1.1 6 0.1* 10.6 6 1.6 1.1 6 0.1* 8.8 6 0.8 1.0 6 0.1* 10.2 6 1.5 2.5 6 0.3y 16.1 6 1.7y Nondiabetic 2.1 6 0.3 15.9 6 3.0 2.3 6 0.5 10.0 6 1.4 1.9 6 0.3 13.6 6 2.0 — — Flow is given in mL/min/100 g and reported as mean 6 SEM. *P \ .01 comparing diabetic dermopathy group with control type 1 diabetic group and nondiabetic control group. y P \ .01 comparing values at diabetic dermopathy sites with uninvolved skin areas in patients with diabetic dermopathy.
Table III. Skin blood flow at reference sites in the 3 groups Type 1 diabetic control
Finger pulp 358C 448C Finger dorsum 358C 448C Toe pulp 358C 448C Toe dorsum 358C 448C Knee 358C 448C Ankle 358C 448C
Diabetic dermopathy
Nondiabetic
40.0 6 2.8 87.0 6 4.9
34.5 6 4.2 85.0 6 6.0
39.8 6 3.3 84.2 6 3.5
13.5 6 1.7 41.9 6 4.4
10.0 6 2.5 37.0 6 5.0
10.1 6 1.3 36.7 6 2.9
17.8 6 2.5 59.4 6 4.2
14.8 6 2.6 48.6 6 5.3
14.2 6 2.1 66.2 6 4.4
3.7 6 0.6 15.1 6 1.6*
2.8 6 0.4 12.5 6 1.5y
3.4 6 0.5 22.4 6 2.5
2.4 6 0.3 14.5 6 1.2*
1.5 6 0.2z 12.3 6 1.2y
1.6 6 0.2 18.9 6 1.7
2.4 6 0.3 13.0 6 1.4
1.4 6 0.1§ 12.4 6 1.8
3.1 6 0.3 14.4 6 2.0
*P \ .05 compared with nondiabetic control group. y P \ .01 compared with nondiabetic control group. z P \ .01 comparing values in diabetic dermopathy group with type 1 diabetic control group. § P \ .01 comparing values in diabetic dermopathy group with both type 1 diabetic control group and nondiabetic group.
group of patients with type 1 diabetes and no evidence of diabetic dermopathy. This decrease in change to blood flow in normal appearing skin sites is clearly demonstrated at 358C, but is also present with maximal skin heating to 448C. Skin sites on the digits of the fingers and toes do not show such differences in skin blood flow, suggesting that there is a functional abnormality at the usual location of dermopathy lesions on the pretibial surface of the legs. The cause of this blood flow abnormality is not clearly apparent. Our patients with diabetic dermopathy had a higher frequency of diabetes-associated complications including retinopathy, microalbuminuria, and neuropathy than the control subjects with
type 1 diabetes. In particular, diabetic neuropathy was present in more than two thirds of the patients with dermopathy but less than 25% of the control diabetic group. It is conceivable that both diabetic microangiopathy and diabetic neuropathy contribute to the functional abnormality in blood flow. Diabetic neuropathy could alter arteriovenous shunting in skin capillaries leading to decreased local skin blood flow. The fact that diabetic dermopathy occurs primarily at the pretibial surface of the legs, an area with nutritive skin flow, rather than at sites endowed with high-density arteriovenous shunt microvessels, tends to argue against this possibility. It is also true that our patients with diabetic dermopathy were older at an average age of 51 years than the control subjects with type 1 diabetes whose average age was 41 years. However, we do not believe that this age difference accounts for the markedly lower blood flow observed in the patients with diabetic dermopathy because in a previous study of the effect of aging on skin blood flow we demonstrated minimal differences in skin blood flow at 358C, comparing volunteers of an average age of 29 years with volunteers of an average age of 76 years.24 Although diabetic dermopathy lesions themselves have increased blood flow, our current findings argue that the scarring of diabetic dermopathy is related to defective skin perfusion. Adequate skin blood flow is essential for proper wound healing.25-27 The pretibial surface of the leg is subject to recurrent minor traumatic events. Other investigators have documented that blood flow is increased in hypertrophic but not atrophic scars.28-31 Studies of burn wounds suggest that wounds that heal rapidly without scarring have higher initial perfusion than those with slow healing.32-34 It is therefore plausible that the decreased blood flow we have demonstrated on the pretibial leg surface predisposes patients with diabetes to inadequate wound healing resulting in formation of the scarring lesions of diabetic dermopathy. Although our results appear to refute the hypothesis that diabetic dermopathy represents local ischemia, it is still plausible that decreased skin blood
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flow leads to the development of diabetic dermopathy. It is possible that an active cutaneous flow is required for healing to proceed with minimal scar formation. A pronounced hyperemic response occurs early in the process of wound healing.25-27 Perhaps skin perfusion in patients with diabetes may be insufficient to heal wounds without scarring. Even minor trauma may lead to scar formation in these patients. This could be the origin of the lesions of diabetic dermopathy. Further studies must focus on this possibility. It remains to be understood why certain patients with type 1 diabetes have lower skin blood flow at the pretibial surface of the legs whereas other patients with type 1 diabetes have normal skin perfusion. We do not know the natural progression of skin blood flow reduction that may lead to an increased scar response resulting in diabetic dermopathy lesions. It would be of interest to carry out long-term longitudinal studies to see if skin blood flow measurement might have predictive value in indicating which patients are susceptible to dermopathy lesions. Finally, if skin blood flow reduction is causal in producing diabetic dermopathy, it may be possible to prevent or treat the process by finding means of increasing local skin perfusion. REFERENCES 1. Melin H. An atrophic circumscribed skin lesion in the lower extremities of diabetics. Acta Med Scand 1964;176(Suppl):1-75. 2. Murphy RA. Skin lesions in diabetic patients: the ‘‘spotted leg’’ syndrome. Lahey Clin Found Bull 1965;14:10-4. 3. Binkley GW, Giraldo B, Stoughton RB. Diabetic dermopathy: a clinical study. Cutis 1967;3:955-8. 4. Danowski TX, Sabeh G, Sarver ME, Shelkrot J, Fisher ER. Shin spots and diabetes mellitus. Am J Med Sci 1966;251:570-5. 5. Bauer M, Levan NE. Diabetic dermangiopathy: a spectrum including pretibial pigmented patches and necrobiosis lipoidica diabeticorum. Br J Dermatol 1970;83:528-35. 6. Huntley AC. Cutaneous manifestations of diabetes mellitus. Dermatol Clin 1989;7:531-46. 7. Jelinek JE. Cutaneous manifestations of diabetes mellitus. Int J Dermatol 1994;33:605-17. 8. Shemer A, Begman R, Linn S, Kantor Y, Friedman-Birnbaum RL. Diabetic dermopathy and internal complications in diabetes mellitus. Int J Dermatol 1998;37:113-5. 9. Rendell M, Bergman T, O’Donnell G, Drobny E, Borgos J, Bonner RF. Microvascular blood flow, volume, and velocity measured by laser Doppler techniques in insulin dependent diabetes. Diabetes 1989;38:819-24. 10. Rendell M, Bamisedun O. Diabetic cutaneous microangiopathy. Am J Med 1992;93:611-8. 11. Rendell M, Saxena S, Shah D. Cutaneous blood flow and peripheral resistance in type II diabetes as compared to intermittent claudication patients. Int J Angiol 2003;12:166-71. 12. Wigington G, Ngo B, Rendell M. Skin blood flow in diabetic dermopathy. Arch Dermatol 2004;140:1248-50. 13. Rendell MS, Dovgan DJ, Bergman TF, O’Donnell GP, Drobny EP, Katims JJ. Mapping diabetic sensory neuropathy by current perception threshold testing. Diabetes Care 1989;12:636-40.
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