Download PDF
Semin Vasc Med 2002; 2(2): 221-228
DOI: 10.1055/s-2002-32045
Copyright © 2002 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

The Diabetic Foot: Pathogenesis and Clinical Evaluation

N. C. Schaper, M. H. Nabuurs-Franssen
  • Department of Internal Medicine and Endocrinology, University Hospital Maastricht, Maastricht, The Netherlands
Further Information

Publication History

Publication Date:
06 June 2002 (online)

    Permissions and Reprints

ABSTRACT

Foot ulcers are one of the major complications of diabetes. They have a poor tendency to heal, which may result in long-term in-hospital treatment and/or amputation. The foot in diabetic patients is the crossroads of several pathological processes, in which almost all components of the lower extremity are involved: skin, subcutaneous tissue, muscles, bones, joints, blood vessels, and nerves. An understanding of these processes is necessary for the development and application of preventative and management strategies. In this article the pathogenesis of the major abnormalities in the diabetic foot are described, the pathways to ulceration are summarized, and a systematic evaluation of a diabetic patient with a foot ulcer is given.

KEYWORDS

Diabetic foot - peripheral polyneuropathy - peripheral vascular disease - wound healing - pathophysiology

REFERENCES

  • 1 Apelqvist J, van Houtum H W, Nabuurs-Franssen M H, Schaper N C. International Consensus on the Diabetic Foot Maastricht, The Netherlands: International Working Group on the Diabetic Foot. 1990: 1-96:1999
    Google Scholar
  • 2 Apelqvist J, Larsson J. What is the most effective way to reduce incidence of amputation in the diabetic foot?.  Diabetes Metab Res Rev . 2000;  S75-S83
    PubMedGoogle Scholar
  • 3 Brod M. Quality of life issues in patients with diabetes and lower extremity ulcers: patients and caregivers.  Qual Life Res . 1998;  7 365-372
    PubMedGoogle Scholar
  • 4 Nabuurs-Franssen M H, van de Berg R, Redekop W. Medical consumption and quality of life of diabetic foot patients in comparison to a background population.  Diabetologia . 2000;  43 A224
    PubMedGoogle Scholar
  • 5 Apelqvist J, Ragnarson-Tennvall G, Larsson J. Long-term costs for foot ulcers in diabetic patients in a multidisciplinary setting.  Foot Ankle Int . 1995;  16 388-394
    PubMedGoogle Scholar
  • 6 Boulton A J, Gries F A, Jervell J A. Guidelines for the diagnosis and outpatient management of diabetic peripheral neuropathy.  Diabet Med . 1998;  15 508-514
    CrossrefPubMedGoogle Scholar
  • 7 Ziegler D. Diagnosis and management of diabetic peripheral neuropathy.  Diabet Med . 1996;  13 S34-S38
    PubMedGoogle Scholar
  • 8 Young M J, Boulton A J, MacLeod A F. A multicentre study of the prevalence of diabetic peripheral neuropathy in the United Kingdom hospital clinic population.  Diabetologia . 1993;  36 150-154
    CrossrefPubMedGoogle Scholar
  • 9 Partanen J, Niskanen L, Lehtinen J. Natural history of peripheral neuropathy in patients with noninsulin-dependent diabetes mellitus.  N Engl J Med . 1995;  333 89-94
    CrossrefPubMedGoogle Scholar
  • 10 Boulton A J. The pathogenesis of diabetic foot problems: an overview.  Diabet Med . 1996;  13 S12-S16
    PubMedGoogle Scholar
  • 11 Simoneau G G, Ulbrecht J S, Derr J A. Postural instability in patients with diabetic sensory neuropathy.  Diabetes Care . 1994;  17 1411-1421
    CrossrefPubMedGoogle Scholar
  • 12 Andersen H, Poulsen P L, Mogensen C E. Isokinetic muscle strength in long-term IDDM patients in relation to diabetic complications.  Diabetes . 1996;  45 440-445
    PubMedGoogle Scholar
  • 13 Andersen H, Gadeberg P C, Brock B. Muscular atrophy in diabetic neuropathy: a stereological magnetic resonance imaging study.  Diabetologia . 1997;  40 1062-1069
    CrossrefPubMedGoogle Scholar
  • 14 Brash P D, Foster J, Vennart W. Magnetic resonance imaging techniques demonstrate soft tissue damage in the diabetic foot.  Diabet Med . 1999;  16 55-61
    CrossrefPubMedGoogle Scholar
  • 15 Cavanagh P R, Ulbrecht J S, Caputo G M. New developments in the biomechanics of the diabetic foot.  Diabetes Metab Res Rev . 2000;  S6-S10
    PubMedGoogle Scholar
  • 16 Frykberg R G, Lavery L A, Pham H. Role of neuropathy and high foot pressures in diabetic foot ulceration.  Diabetes Care . 1998;  21 1714-1719
    PubMedGoogle Scholar
  • 17 Veves A, Murray H J, Young M J. The risk of foot ulceration in diabetic patients with high foot pressure: a prospective study.  Diabetologia . 1992;  35 660-663
    CrossrefPubMedGoogle Scholar
  • 18 Ahroni J H, Boyko E J, Forsberg R C. Clinical correlates of plantar pressure among diabetic veterans.  Diabetes Care . 1999;  22 965-972
    PubMedGoogle Scholar
  • 19 Fernando D J, Masson E A, Veves A. Relationship of limited joint mobility to abnormal foot pressures and diabetic foot ulceration.  Diabetes Care . 1991;  14 8-11
    CrossrefPubMedGoogle Scholar
  • 20 Abouaesha F, van Schie H C, Griffths G D. Plantar tissue thickness is related to peak plantar pressure in the high-risk diabetic foot.  Diabetes Care . 2001;  24 1270-1274
    PubMedGoogle Scholar
  • 21 Murray H J, Young M J, Hollis S. The association between callus formation, high pressures and neuropathy in diabetic foot ulceration.  Diabet Med . 1996;  13 979-982
    CrossrefPubMedGoogle Scholar
  • 22 Masson E A, Hay E M, Stockley I. Abnormal foot pressures alone may not cause ulceration.  Diabet Med . 1989;  6 426-428
    PubMedGoogle Scholar
  • 23 Cavanagh P R, Ulbrecht J S, Caputo G M. What the practising physician should know about diabetic foot biomechanics. In: Boulton AJ, Connor H, Cavanagh PR, et al., eds. The Foot in Diabetes 3rd ed. Chichester, England: Wiley; 2000: 33-59
    Google Scholar
  • 24 Apelqvist J, Larsson J, Agardh C D. The influence of external precipitating factors and peripheral neuropathy on the development and outcome of diabetic foot ulcers.  J Diabetes Complications . 1990;  4 21-25
    PubMedGoogle Scholar
  • 25 Schaper N C, Nabuurs-Franssen M H, Huijberts M S. Peripheral vascular disease and type 2 diabetes mellitus.  Diabetes Metab Res Rev . 2000;  S11-S15
    PubMedGoogle Scholar
  • 26 Garcia M J, McNamara P M, Gordon T. Morbidity and mortality in diabetics in the Framingham population. Sixteen-year follow-up study.  Diabetes . 1974;  23 105-111
    CrossrefPubMedGoogle Scholar
  • 27 Clausell N, Kalil P, Biolo A. Increased expression of tumor necrosis factor-alpha in diabetic macrovasculopathy.  Cardiovasc Pathol . 1999;  8 145-151
    CrossrefPubMedGoogle Scholar
  • 28 Conrad M C. Large and small artery occlusion in diabetics and nondiabetics with severe vascular disease.  Circulation . 1967;  36 83-91
    CrossrefPubMedGoogle Scholar
  • 29 Osmundson P J, O'Fallon W M, Zimmerman B R. Course of peripheral occlusive arterial disease in diabetes. Vascular laboratory assessment.  Diabetes Care . 1990;  13 143-152
    PubMedGoogle Scholar
  • 30 Beach K W, Bedford G R, Bergelin R O. Progression of lower-extremity arterial occlusive disease in type II diabetes mellitus.  Diabetes Care . 1988;  11 464-472
    PubMedGoogle Scholar
  • 31 Hansen M E, Valentine R J, McIntire D D. Age-related differences in the distribution of peripheral atherosclerosis: when is atherosclerosis truly premature?.  Surgery . 1995;  118 834-839
    PubMedGoogle Scholar
  • 32 TransAtlantic Inter-Society Consensus (TASC). Management of peripheral arterial disease (PAD).  Eur J Vasc Endovasc Surg . 2000;  S1-S250
    PubMedGoogle Scholar
  • 33 McDaniel M D, Cronenwett J L. Basic data related to the natural history of intermittent claudication.  Ann Vasc Surg . 1989;  3 273-277
    CrossrefPubMedGoogle Scholar
  • 34 Laakso M. Hyperglycemia and cardiovascular disease in type 2 diabetes.  Diabetes . 1999;  48 937-942
    CrossrefPubMedGoogle Scholar
  • 35 Forrest K Y, Becker D J, Kuller L H. Are predictors of coronary heart disease and lower-extremity arterial disease in type 1 diabetes the same?.  <~>A prospective study. Atherosclerosis . 2000;  148 159-169
    PubMedGoogle Scholar
  • 36 Price J F, Mowbray P I, Lee A J. Relationship between smoking and cardiovascular risk factors in the development of peripheral arterial disease and coronary artery disease: Edinburgh Artery Study.  Eur Heart J . 1999;  20 344-353
    CrossrefPubMedGoogle Scholar
  • 37 Cerami C. Tobacco smoke is a source of toxic reactive glycation products.  Proc Natl Acad Sci USA . 1997;  94
    PubMedGoogle Scholar
  • 38 Vigna G B, Fellin R. Dyslipidemia in peripheral vascular disease.  Curr Opin Lipidol . 1996;  7 254-259
    PubMedGoogle Scholar
  • 39 O'Neal D N, Lewicki J, Ansari M Z. Lipid levels and peripheral vascular disease in diabetic and nondiabetic subjects.  Atherosclerosis . 1998;  136 1-8
    CrossrefPubMedGoogle Scholar
  • 40 Pedersen T R, Kjekshus J, Pyörälä K. Effect of simvastatin on ischemic signs and symptoms in the Scandinavian simvastatin survival study (4S).  Am J Cardiol . 1998;  81 333-335
    CrossrefPubMedGoogle Scholar
  • 41 MacGregor A S, Price J F, Hau C M. Role of systolic blood pressure and plasma triglycerides in diabetic peripheral arterial disease. The Edinburgh Artery Study.  Diabetes Care . 1999;  22 453-458
    CrossrefPubMedGoogle Scholar
  • 42 Hoogeveen E K, Kostense P J, Jakobs C. Hyperhomocysteinaemia is not associated with isolated crural arterial occlusive disease: The Hoorn Study.  J Intern Med . 2000;  247 442-448
    CrossrefPubMedGoogle Scholar
  • 42a Hovind P, Tarnow L, Teerlinz T, Stehouwer C D, Emeis J J, Parving H H. Progression of diabetic nephropathy: role of plasma homocysteine and plasminogen activator inhibitor-1.  Am J Kidney Dis . 2001;  38 1376-1380
    PubMedGoogle Scholar
  • 43 Smulders Y M, Rakic M, Slaats E H. Fasting and post-methionine homocysteine levels in NIDDM. Determinants and correlations with retinopathy, albuminuria, and cardiovascular disease.  Diabetes Care . 1999;  22 125-132
    PubMedGoogle Scholar
  • 44 Ross R. Atherosclerosis-an inflammatory disease.  N Engl J Med . 1999;  340 115-126
    CrossrefPubMedGoogle Scholar
  • 45 Ridker P M, Cushman M, Stampfer M J. Plasma concentration of C-reactive protein and risk of developing peripheral vascular disease.  Circulation . 1998;  97 425-428
    CrossrefPubMedGoogle Scholar
  • 46 Fiotti N, Giansante C, Ponte E. Atherosclerosis and inflammation. Patterns of cytokine regulation in patients with peripheral arterial disease.  Atherosclerosis . 1999;  145 51-60
    CrossrefPubMedGoogle Scholar
  • 47 Blann A D, McCollum C N. Increased levels of soluble tumor necrosis factor receptors in atherosclerosis: no clear relationship with levels of tumor necrosis factor.  Inflammation . 1998;  22 483-491
    CrossrefPubMedGoogle Scholar
  • 48 Matsumoto K, Miyake S, Yano M. Insulin resistance and arteriosclerosis obliterans in patients with NIDDM.  Diabetes Care . 1997;  20 1738-1743
    PubMedGoogle Scholar
  • 49 Price J F, Lee A J, Fowkes F G. Hyperinsulinaemia: a risk factor for peripheral arterial disease in the nondiabetic general population.  J Cardiovasc Risk . 1996;  3 501-505
    PubMedGoogle Scholar
  • 50 Houben A J, Nieuwenhuijzen Kruseman C A, Bouhouch E. Peripheral macro- and microcirculation in short-term insulin-dependent diabetes mellitus: the role of prostaglandins in early haemodynamic changes.  Eur J Clin Invest . 1993;  23 662-667
    PubMedGoogle Scholar
  • 51 Sandeman D D, Shore A C, Tooke J E. Relation of skin capillary pressure in patients with insulin-dependent diabetes mellitus to complications and metabolic control.  N Engl J Med . 1992;  327 760-764
    PubMedGoogle Scholar
  • 52 Jaap A J, Shore A C, Gartside I B. Increased microvascular fluid permeability in young type 1 (insulin-dependent) diabetic patients.  Diabetologia . 1993;  36 648-652
    CrossrefPubMedGoogle Scholar
  • 53 Flynn M D, Tooke J E. Diabetic neuropathy and the microcirculation.  Diabet Med . 1995;  12 298-301
    CrossrefPubMedGoogle Scholar
  • 54 Rayman G, Williams S A, Gamble J. A study of factors governing fluid filtration in the diabetic foot.  Eur J Clin Invest . 1994;  24 830-836
    PubMedGoogle Scholar
  • 55 Shore A C, Jaap A J, Tooke J E. Capillary pressure in patients with NIDDM.  Diabetes . 1994;  43 1198-1202
    PubMedGoogle Scholar
  • 56 Jaap A J, Shore A C, Gamble J. Capillary filtration coefficient in type II (noninsulin-dependent) diabetes.  J Diabetes Complications . 1994;  8 111-116
    PubMedGoogle Scholar
  • 57 Nabuurs-Franssen M H, Houben A J, Dennert J. The effect of polyneuropathy of the foot microcirculation in type 2 diabetes.  Diabetologia . 2001;  44 A1065
    CrossrefPubMedGoogle Scholar
  • 58 Jaap A J, Hammersley M S, Shore A C. Reduced microvascular hyperaemia in subjects at risk of developing type 2 (noninsulin-dependent) diabetes mellitus.  Diabetologia . 1994;  37 214-216
    CrossrefPubMedGoogle Scholar
  • 59 Netten P M, Wollersheim H, Thien T. Skin microcirculation of the foot in diabetic neuropathy.  Clin Sci (Lond) . 1996;  91 559-565
    PubMedGoogle Scholar
  • 60 Dyer D G, Dunn J A, Thorpe S R. Accumulation of Maillard reaction products in skin collagen in diabetes and aging.  J Clin Invest . 1993;  91 2463-2469
    CrossrefPubMedGoogle Scholar
  • 61 Mowat A, Baum J. Chemotaxis of polymorphonuclear leukocytes from patients with diabetes mellitus.  N Engl J Med . 1971;  284 621-627
    PubMedGoogle Scholar
  • 62 Davidson N J, Sowden J M, Fletcher J. Defective phagocytosis in insulin controlled diabetics: evidence for a reaction between glucose and opsonising proteins.  J Clin Pathol . 1984;  37 783-786
    PubMedGoogle Scholar
  • 63 Repine J E, Clawson C C, Goetz F C. Bactericidal function of neutrophils from patients with acute bacterial infections and from diabetics.  J Infect Dis . 1980;  142 869-875
    PubMedGoogle Scholar
  • 64 Boland O M, Blackwell C C, Clarke B F. Effects of ponalrestat, an aldose reductase inhibitor, on neutrophil killing of Escherichia coli and autonomic function in patients with diabetes mellitus.  Diabetes . 1993;  42 336-340
    PubMedGoogle Scholar
  • 65 Fahey III J T, Sadaty A, Jones II G W. Diabetes impairs the late inflammatory response to wound healing.  J Surg Res . 1991;  50 308-313
    CrossrefPubMedGoogle Scholar
  • 66 Goova M T, Li J, Kislinger T. Blockade of receptor for advanced glycation end-products restores effective wound healing in diabetic mice.  Am J Pathol . 2001;  159 513-525
    CrossrefPubMedGoogle Scholar
  • 67 Rowe D W, Starman B J, Fujimoto W Y. Abnormalities in proliferation and protein synthesis in skin fibroblast cultures from patients with diabetes mellitus.  Diabetes . 1977;  26 284-290
    PubMedGoogle Scholar
  • 68 Loots M A, Lamme E N, Mekkes J R. Cultured fibroblasts from chronic diabetic wounds on the lower extremity (noninsulin-dependent diabetes mellitus) show disturbed proliferation.  Arch Dermatol Res . 1999;  291 93-99
    CrossrefPubMedGoogle Scholar
  • 69 Loots M AM, Kenter S B, Au A L. Fibroblast derived from chronic diabetic ulcers differ in their response to stimulation with AGF, IGF-1, bFGF and PDGF-AB compared to controls.  Eur J Cell Biol. In press.
    PubMedGoogle Scholar
  • 70 Edmonds M, Bates M, Doxford M. New treatments in ulcer healing and wound infection.  Diabetes Metab Res Rev . 2000;  S51-S54
    PubMedGoogle Scholar
  • 71 Reiber G E, Vileikyte L, Boyko E J. Causal pathways for incident lower-extremity ulcers in patients with diabetes from two settings.  Diabetes Care . 1999;  22 157-162
    CrossrefPubMedGoogle Scholar
  • 72 Apelqvist J, Bakker K, van Houtum H W. International consensus and practical guidelines on the management and the prevention of the diabetic foot. International Working Group on the Diabetic Foot.  Diabetes Metab Res Rev . 2000;  S84-S92
    PubMedGoogle Scholar
  • 73 Schaper N C, Van Putten A M. Do diabetologists adequately detect patients at risk for amputation?.  Diabetologia . 2001;  44 A1076
    PubMedGoogle Scholar
  • 74 Armstrong D G, Lavery L A, Harkless L B. Validation of a diabetic wound classification system. The contribution of depth, infection, and ischemia to risk of amputation.  Diabetes Care . 1998;  21 855-859
    CrossrefPubMedGoogle Scholar
  • 75 Grayson M L, Gibbons G W, Balogh K. Probing to bone in infected pedal ulcers. A clinical sign of underlying osteomyelitis in diabetic patients.  JAMA . 1995;  273 721-723
    CrossrefPubMedGoogle Scholar
  • 76 de Heus-van Putten A M, Schaper N C, Bakker K. The clinical examination of the diabetic foot in daily practise.  Diabet Med . 1996;  13 S55-S57
    PubMedGoogle Scholar
  • 77 McGee S R, Boyko E J. Physical examination and chronic lower-extremity ischemia: a critical review.  Arch Intern Med . 1998;  158 1357-1364
    CrossrefPubMedGoogle Scholar
  • 78 Jorneskog G, Brismar K, Fagrell B. Skin capillary circulation is more impaired in the toes of diabetic than nondiabetic patients with peripheral vascular disease.  Diabet Med . 1995;  12 36-41
    PubMedGoogle Scholar
  • 79 Pecoraro R E, Ahroni J H, Boyko E J. Chronology and determinants of tissue repair in diabetic lower-extremity ulcers.  Diabetes . 1991;  40 1305-1313
    PubMedGoogle Scholar
  • 80 Kalani M, Brismar K, Fagrell B. Transcutaneous oxygen tension and toe blood pressure as predictors for outcome of diabetic foot ulcers.  Diabetes Care . 1999;  22 147-151
    PubMedGoogle Scholar
  • 81 Ho K Y, Leiner T, de Haan W M. Peripheral vascular tree stenoses: evaluation with moving-bed infusion-tracking MR angiography.  Radiology . 1998;  206 683-692
    PubMedGoogle Scholar
  • 82 Rith-Najarian S J, Stolusky T, Gohdes D M. Identifying diabetic patients at high risk for lower-extremity amputation in a primary health care setting. A prospective evaluation of simple screening criteria.  Diabetes Care . 1992;  15 1386-1389
    CrossrefPubMedGoogle Scholar
  • 83 McGill M, Molyneaux L, Yue D K. Use of the Semmes-Weinstein 5.07/10-gram monofilament: the long and the short of it.  Diabet Med . 1998;  15 615-617
    CrossrefPubMedGoogle Scholar
  • 84 Eneroth M, Apelqvist J, Stenstrom A. Clinical characteristics and outcome in 223 diabetic patients with deep foot infections.  Foot Ankle Int . 1997;  18 716-722
    PubMedGoogle Scholar
  • 85 Lipsky B A, Berendt A R. Principles and practice of antibiotic therapy of diabetic foot infections.  Diabetes Metab Res Rev . 2000;  S42-S46
    PubMedGoogle Scholar
  • 86 Eneroth M, Larsson J, Apelqvist J. Deep foot infections in patients with diabetes and foot ulcer: an entity with different characteristics, treatments, and prognosis.  J Diabetes Complications . 1999;  13 254-263
    CrossrefPubMedGoogle Scholar
  • 87 Rauwerda J A. Foot debridement: anatomic knowledge is mandatory.  Diabetes Metab Res Rev . 2000;  S23-S26
    PubMedGoogle Scholar
  • 88 Craig J G, Amin M B, Wu K. Osteomyelitis of the diabetic foot: MR imaging-pathologic correlation.  Radiology . 1997;  203 849-855
    CrossrefPubMedGoogle Scholar