CLINICAL EVENTS CALENDAR
- Nov 18,2009Nov 21,2009Yucatan Pediatric Seminar11/18/2009 - 12:2111/21/2009 - 12:21
Northwest Podiatric Foundation
Yucatan Crippled Children's Project
Merida, Mexico
Hyatt Regency Merida Hotel
1-866-286-NWPF - Jan 10,2010Jan 17,2010Winter Seminar at Sea01/10/2010 - 12:2401/17/2010 - 12:24
Northwest Podiatric Foundation
Southern Caribbean Cruise
RCCL - The Adventure of the Seas
1-866-286-NWPF - Apr 17,2010Apr 20,20102010 SAWC Spring04/17/2010 - 11:2304/20/2010 - 11:23website:
Gaylord Palms Hotel and Convention Center
Orlando, FL - Jul 15,2010Jul 18,2010The 2010 APMA Annual Scientific Meeting07/15/2010 - 13:2607/18/2010 - 13:26website:
Washington State Convention & Trade Center
Seattle, Washington
Non-Accredited Education
Managing the Diabetic Foot: A Clinical and Economic View Complimentary Archived Webcast
Non-Accredited
Understanding Collagen Dressings and their Benefit in Wound Care![]()
Complimentary Archived Webcast
non-accredited
Introduction
Dr. Allie is the Director of Cardiothoracic and Endovascular Surgery at the Cardiovascular Institute of the South in Lafayette, Louisiana.
The true relevance, natural history, clinical impact, and social and economic costs of diabetic neuropathy are not well documented because of inconsistencies in the objective diagnostic criteria. Certainly, the incidence must be significant with the increasing incidence of diabetes (14–16 million), obesity, peripheral arterial disease (PAD), and elderly population. The cardiovascular complications of diabetes are staggering with end-stage lower-extremity PAD and diabetes resulting in the development of critical limb ischemia (CLI), which causes 220,000–240,000 amputations yearly in the United States and Europe.1–6 The patient with diabetes is at 7–40 times greater risk for amputation than the patient without diabetes, and increasingly, diabetic neuropathy is being implicated as a contributing factor.6
The etiological pathophysiologic mechanism of diabetic neuropathy is considered multifactorial and includes direct metabolic injury to the nerve fiber, impaired neuropathic regeneration, and neurovascular insufficiency including direct endothelial injury and dysfunction caused by reduced nitric oxide (NO) availability and disrupted normal cellular oxidation. Homocysteine, a sulfhydryl amino acid, has been strongly associated with cardiovascular disease, especially PAD, and most recently has been implicated in diabetic neuropathy. Elevated homocysteine levels are also associated with endothelial dysfunction, decreased NO, and, therefore, impaired wound and tissue healing because optimal NO bioavailability is necessary for angiogenesis, collagen deposition, and granulation tissue formation.7–11 Normal homocysteine metabolism requires remethylation and transulfuration with vitamin B6, vitamin B12, and folate as essential cofactors. Hyperhomocysteinemia can be inherited (a TT-genotype, which reduces folic acid metabolism) or acquired due to nutritional (vitamin) deficiencies. Cigarette smoking and excessive caffeine consumption have been associated with hyperhomocysteinemia.
Clinically, diabetic neuropathy has been associated with the duration of diabetes, insulin dependency, and poor glycemic control (elevated HbA1c).12 Optimizing insulin therapy has shown modest improvements by vibratory sensitivity and nerve conduction velocity but in general medical and surgical treatment for diabetic neuropathy can be characterized as poor, and it is considered irreversible in most cases. The recent understanding of the role of NO, homocysteine metabolism, and its cofactors has given rise to several novel medical strategies to treat diabetic neuropathy, PAD, and impaired wound healing.13 Oral 6(S)-methyltetrahydrofolate (L-MTHF), the active form of folic acid, has been shown to increase NO synthesis therefore reducing superoxide generation with improved endothelial function. L-methylfolate has several distinct advantages over oral folic acid administration including being 7 times more bioavailable with a significant superiority (3 times) in lowering serum homocysteine.13,14 These advantages are achieved as the metabolically active L-methylfolate avoids the complex 4-step conversion process oral folic acid must go through for activation. Additionally, 40–50% of the patient population exhibits a genetic polymorphism in which folic acid is incompletely converted to L-methylfolate.14–17 Pyridoxal 5’-phosphate (vitamin B6) and methylcobalamin (vitamin B12) are important in maintaining neurofunctions, including myelinogenesis, nerve repair, and nerve regeneration, which are impaired in severe diabetic neuropathy.10
Serum vitamin levels have been associated with serum homocysteine levels. A strong inverse relationship exists between plasma homocysteine and both folic acid and vitamin B12 therefore creating an opportunity for a medical (nutritional) strategy for treating diabetic neuropathy. Metanx (Pamlab, L.L.C., Covington, La) has combined 2.8 mg L-methylfolate, 25 mg pyridoxal 5’-phosphate, and 2 mg methylcobalamin into 1 novel supplement, optimizing a strategy to treat hyperhomocysteinemia and its clinical sequelae, including diabetic neuropathy, with potential for far reaching benefits in other diabetic complications including cardiovascular disease, PAD, and even CLI. Several illustrative clinical cases are presented using these novel treatment strategies in treating diabetic neuropathy.
References
1. Fisher RK, Harris PL. Epidemiological and economic considerations in the critically ischemic limb. In: Branchereau A, Jacobs M, eds. Critical Limb Ischemia. Armonk, NY: Futura Publishing Company, Inc; 1999:19–25.
2. Anonymous. Second European Consensus Document on chronic critical limb ischemia. Eur J Vasc Surg. 1992;6(Suppl A):1–32.
3. Yost ML. Peripheral Arterial Disease: A Report by The Sage Group. 2004; Vol. II.
4. Mayfield JA, Reiber GE, Maynard C, Czerniecki JM, Caps MT, Sangeorzan BJ. Trends in lower limb amputation in Veterans Health Administration, 1989–1998. J Rehabil Res Dev. 2000;37(1):23–30.
5. US Department of Health and Human Services. National Center for Health Statistics. National Hospital Discharge Survey: 1983–2000 Annual Summary with Detailed Diagnosis and Procedure Data. Data from the National Hospital Discharge Survey. Series 13.
6. Allie DE, Hebert CJ, Lirtzman MD, et al. Critical limb ischemia: a global epidemic. A critical analysis of current treatment unmasks the clinical and economic costs of CLI. Euro Intervention. 2005;1(1):75–84.
7. Starkebaum G, Harlan JM. Endothelial cell injury due to copper-catalyzed hydrogen peroxide generation from homocysteine. J Clin Invest. 1986;77(4):1370–1376.
8. Stamler JS, Osborne JA, Jaraki O, et al. Adverse vascular effects of homocysteine are modulated by endothelial-derived relaxing factor and related oxides of nitrogen. J Clin Invest. 1993;91(1):308–318.
9. Ambrosch A, Dierkes J, Lobmann R, et al. Relation between homocysteinaemia and diabetic neuropathy in patients with Type 2 diabetes mellitus. Diabet Med. 2001;18(3):185–192.
10. Yaqub BA, Siddique A, Sulimani R. Effects of methylcobalamin on diabetic neuropathy. Clin Neurol Neurosurg. 1992;94(2):105–111.
11. Mangoni AA, Sherwood RA, Asonganyi B, Swift CG, Thomas S, Jackson SH. Short-term oral folic acid supplementation enhances endothelial function in patients with type 2 diabetes. Am J Hypertens. 2005;18(2 Pt 1):220–226.
12. The DCCT Research Group. Factors in the development of diabetic neuropathy. Baseline analysis of neuropathy in feasibility phase of Diabetes Control and Complications Trial (DCCT). Diabetes. 1988;37(4):476–481.
13. Boykin JV Jr, Baylis C, Allen SK, et al. Treatment of elevated homocysteine to restore normal wound healing: a possible relationship between homocysteine, nitric oxide, and wound repair. Adv Skin Wound Care. 2005;18(6):297–300.
14. Venn BJ, Green TJ, Moser R, Mann JI. Comparison of the effect of low-dose supplementation with L-5 methyltetrahydrofolate or folic acid on plasma homocysteine: a randomized placebo-controlled study. Am J Clin Nutr. 2003;77(3):658–662.
15. Deloughery TG, Evans A, Sadeghi A, et al. Common mutation in methylenetetrahydrofolate reductase. Correlation with homocysteine metabolism and late-onset vascular disease. Circulation. 1996;94(12):3074–3078.
16. Klerk M, Verhoef P, Clarke R, Blom HJ, Kok FJ, Schouten EG; MTHFR Studies Collaboration Group. MTHFR 677C-->T polymorphism and risk of coronary heart disease: a meta-analysis. JAMA. 2002;288(16):2023–2031.
17. Willems FF, Boers GH, Blom HJ, Aengevaeren WR, Verheugt FW. Pharmacokinetic study on the utilisation of 5-methyltetrahydrofolate and folic acid in patients with coronary artery disease. Br J Pharmacol. 2004;141(5):825–830.
William Fishco, DPM, FACFAS
Michelle L. Butterworth, DPM, FACFAS
Lake Charles, Louisiana
Hampton Bays and Long Island, New York
Various Locations- Indiana , Ohio
CME Showcase
"Current Concepts In Healing Chronic Diabetic Foot Ulcerations"
A Complimentary On-Demand CE/CME Webcast This activity is supported by an educational grant from Advanced Biohealing. To access this Webcast, visit www.naccme.com/program/n-550/ |
![]() Current Concepts In Diagnosing And Treating MRSA In The Diabetic Foot This activity is supported by an education grant from Pfizer. To access this activity, visit www.naccme.com/program/n-528/ |
MRSA And Diabetic Foot Wounds: Where Do We Go From Here?Archived Accredited Webcast with Q&A This activity is supported by an educational grant from Pfizer. This activity is sponsored by the North American Center For Continuing Medical Education (NACCME). |
Managing Vascular and Wound Healing Challenges with Current and Emerging Technologies Archived Accredited Webcast with Q&A This activity is supported by an educational grant from Baxter Healthcare Corporation. |
Podiatry Today News Wire
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