Diabetic Foot Ulcers: Pathogenesis and Prevention

March 19, 2015

By Shilpa Mukunda, MD

Peer Reviewed

On my first day on inpatient medicine at the VA Hospital, Mr. P came in with an oozing foot ulcer. Mr. P, a 60-year-old man with a 30 pack-year smoking history, poorly controlled diabetes, peripheral vascular disease, and chronic renal disease, had already had toes amputated. He knew all too well the routine of what would happen now with his newest ulcer. After two weeks of IV antibiotics and waiting for operating room time, Mr. P eventually had his toe amputated. It was his fourth amputation.

Mr. P unfortunately is not alone in this chronic complication of diabetes. Approximately 15-25% of individuals with type 2 diabetes mellitus develop a diabetic foot ulcer [1]. Not all ulcers, however, require amputation. Ulcers can also be treated with sharp debridement, offloading techniques to redistribute pressure from the ulcer, and wound dressings, with hydrogels being the most frequently used [2]. Weekly sharp debridement is associated with more rapid healing of ulcers [2]. In addition, in patients with severe peripheral vascular disease and critical limb ischemia, early surgical revascularization can prevent ulcer progression and decrease rates of amputation [3]. Even with immediate and intensive treatment, however, many foot ulcers will take months to heal or may not heal at all. Diabetic foot ulcers are the most common cause of non-traumatic amputations in the United States, with 14-24% of patients with an ulcer subsequently undergoing amputation [4]. Amputation leads to physical disability and greatly reduced quality of life [5]. In addition to their detrimental effects on the lives of individual patients, ulcers also have a great economic cost to society. Patients with ulcers often have lengthy inpatient stays with involvement of specialists. According to a 1999 study, the healthcare costs of a single ulcer are estimated to be approximately $28,000 [4].

The pathogenesis of diabetic foot ulcers is multifaceted. Neuropathy, abnormal foot mechanics, peripheral artery disease, and poor wound healing contribute to diabetic foot ulcers. Neuropathy, a microvascular complication of diabetes, occurs in approximately 50% of individuals with long-standing type 1 and type 2 diabetes mellitus, and causes diabetic foot ulcers through a variety of mechanisms [6]. First, distal symmetric polyneuropathy of sensory fibers, the most common neuropathy in diabetes, leads to distal sensory loss in a glove-and-stocking distribution. Without the ability to sense pain, patients with diabetic neuropathy can inadvertently sustain repeated trauma to the foot. Neuropathy can also manifest with disordered proprioception, resulting in improper weight bearing and ulceration [6]. Motor and sensory neuropathy together can lead to disordered foot mechanics, manifesting variably as hammertoe, claw toe deformity, and Charcot foot. These structural changes cause abnormal pressure points and increased shear stress on the foot, both of which increase the risk for ulcer formation [7]. Diabetic neuropathy can also affect autonomic fibers. Autonomic neuropathy results in decreased sweating of the foot and dry skin, leading to cracks and fissures that can serve as entry points for bacteria [1]. In addition to neuropathy, many diabetics have peripheral artery disease, a macrovascular complication of diabetes and an independent risk factor for lower extremity amputation [8]. Peripheral artery disease leads to decreased tissue perfusion, which then impedes wound healing. In addition, impaired cell-mediated immunity and phagocyte function further reduce wound healing in diabetics [6]. A study by Lavery and colleagues found that the risk of ulceration in diabetics was proportional to the number of risk factors, with the risk increased by 1.7 in diabetics with isolated peripheral neuropathy and by 36 in diabetics with peripheral neuropathy, deformity, and a previous amputation [9].

How can ulcers be prevented? Optimizing glycemic control is the most important initial step. One study found that the risk of an ulcer increased in direct proportion to each 1% rise in the hemoglobin A1c [10]. In the primary care setting, diabetic patients should be screened for foot ulcers annually, with higher-risk patients screened more frequently. The annual foot exam should include visual inspection of the feet for calluses, skin integrity, and bony deformities. Patients with ulcerations or gross deformities should be referred to a podiatrist. The foot exam should also include screening for loss of protective sensation with the Semmes-Weinstein monofilament. Inability to perceive the 10-gram load imparted by the filament is associated with large-fiber neuropathy and a 7-fold increase in the risk of ulceration [11]. In addition, diabetic patients should be screened for peripheral vascular disease through palpation of the dorsalis pedis and posterior tibialis pulses and measurement of ankle-brachial index. Patients with peripheral vascular disease should be given additional counseling on smoking cessation, as smoking worsens peripheral artery disease, and referral to a vascular surgeon should be considered. All diabetic patients, especially those who have lost monofilament sensation, should be educated about foot precautions, including daily inspection of the toes and feet, wearing well-fitting socks and shoes, and keeping the skin clean and moist [12]. A 2014 Cochrane review of patient education for preventing diabetic foot ulceration found that foot care knowledge and self-reported patient behavior are positively influenced by education in the short term, yet robust evidence is lacking to show that education alone can achieve clinically relevant reductions in ulcer and amputation incidence [13]. While patient education alone may not be enough to prevent ulcers, studies have shown that multidisciplinary foot care involving physicians, educators, podiatrists, surgeons, home care nurses, nutritionists, and social services can lead to improved outcomes [14]. In Sweden, patients with diabetes managed with a multidisciplinary approach had a 50% reduction (7.9/1000 to 4.1/1000) in amputations over 11 years [15].

As the number of people living with diabetes is rising, with an estimated 300 million people with diabetes by 2025 [14], the complications associated with diabetes are also likely to increase. Despite this rise in numbers, it is important to note that major amputation rates among diabetics are falling, as shown in a 2006 study in Helsinki [3]. This is likely due to preventive measures with improved glycemic control, establishment of diabetic multidisciplinary teams, and earlier vascular revascularization procedures [3]. Ultimately, prevention is the best approach to diabetic foot ulcers. It is our goal as physicians to ensure that all our diabetic patients can live long lives with all 10 toes intact. That goal is ambitious but possible.

Dr. Shilpa Mukunda is a 1st year Internal Medicine resident at Boston University

Peer reviewed by Robert Lind, MD, Internal Medicine, NYU Langone Medical Center

Image courtesy of Wikimedia Commons


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2. Yazdanpanah L, Nasiri M, Adarvishi S. Literature review on the management of diabetic foot ulcer. World J Diabetes. 2015;6(1):37-53.

3. Eskelinen E, Eskelinen A, Albäck A, Lepäntalo M. Major amputation incidence decreases both in non-diabetic and in diabetic patients in Helsinki. Scand J Surg. 2006;95(3):185-189.

4. Ramsey SD, Newton K, Blough D, et al. Incidence, outcomes, and cost of foot ulcers in patients with diabetes. Diabetes Care. 1999;22(3):382-387.  http://www.ncbi.nlm.nih.gov/pubmed/10097914

5. Consensus Development Conference on Diabetic Foot Wound Care: 7–8 April 1999, Boston, Massachusetts. American Diabetes Association. Diabetes Care. 1999;22(8):1354-1360.  http://www.ncbi.nlm.nih.gov/pubmed/10480782

6. Powers AC. Diabetes mellitus. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 18th ed. New York: McGraw-Hill; 2012. http://www.accessmedicine.com/content.aspx?aID=9141196. Accessed November 19, 2012.

7. Sumpio B. Foot ulcers. N Engl J Med. 2000;343(11):787-793.

8. Adler AI, Boyko EJ, Ahroni JH, Smith DG. Lower-extremity amputation in diabetes. The independent effects of peripheral vascular disease, sensory neuropathy, and foot ulcers. Diabetes Care. 1999;22(7):1029-1035.

9. Lavery LA, Armstrong DG, Vela SA, Quebedeaux TL, Fleischli JG. Practical criteria for screening patients at high risk for diabetic foot ulceration. Arch Intern Med. 1998;158(2):157-162.

10. Boyko EJ, Ahroni JH, Cohen V Nelson KM, Heagerty PJ. Prediction of diabetic foot ulcer occurrence using commonly available clinical information: the Seattle Diabetic Foot Study. Diabetes Care. 2006;29(6):1202-1207.  http://www.ncbi.nlm.nih.gov/pubmed/16731996

11. McNeely MJ, Boyko EJ, Ahroni JH, et al. The independent contributions of diabetic neuropathy and vasculopathy in foot ulceration: how great are the risks? Diabetes Care. 1995;18(2):216-219.

12. Calhoun JH, Overgaard KA, Stevens CM, Dowling JP, Mader JT. Diabetic foot ulcers and infections: current concepts. Adv Skin Wound Care. 2002;15(1):31-42.

13. Dorresteijn JA, Kriegsman DM, Assendelft WJ, Valk GD. Patient education for preventing diabetic foot ulceration. Cochrane Database Syst Rev. 2014;12:CD001488. http://www.ncbi.nlm.nih.gov/pubmed/20464718

14. Bartus CL, Margolis DJ. Reducing the incidence of foot ulceration and amputation in diabetes. Curr Diab Rep. 2004;4(6):413-418. http://www.ncbi.nlm.nih.gov/pubmed/15539004

15. Larsson J, Apelqvist J, Agardh CD, Stenström A. Decreasing incidence of major amputation in diabetic patients: a consequence of a multidisciplinary foot care team approach? Diabet Med. 1995;12(9):770–776. http://www.ncbi.nlm.nih.gov/pubmed/8542736


One comment on “Diabetic Foot Ulcers: Pathogenesis and Prevention

  • Avatar of Dr. Linda Benskin
    Dr. Linda Benskin on

    I have written a detailed heavily footnoted Diabetic Foot Ulcer Clinical Education booklet which summarizes all of the research to date about the prevention and management of diabetic foot ulcers. There is very good evidence, for example, for preventing ulceration by aggressively offloading hotspots, which can be identified by patients using a simple hand held thermometer. A better design would be a device on which patients could stand every morning. Any inventors out there with the capital to produce such a device are welcome to patent and use the idea.

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