subjects at risk for type 2 diabetes. Diabetes 1999;48:1856, 1862. 40. Krishnan ST, Baker NR, Carrington AL, Rayman G. Comparative roles of microvascular and nerve function in foot ulceration in type 2 diabetes. Diabetes Care 2004;27:1343, 1348. 41. Rayman G, Baker NR, Krishnan STM. Wound healing and microvascular responses in the foot skin of type 2 diabetic subjects with neuropathy. Diabetic Foot Study Group, 5th Scientific Meeting; 2005; Chalkidiki, Greece.
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5 The Pathway to Ulceration: Aetiopathogenesis Andrew J.M. Boulton
Coming events cast their shadows before , Thomas Campbell
INTRODUCTION As the lifetime incidence of foot ulceration in diabetic patients was recently estimated to be as high as 25%,1 understanding the pathways that result in the development of an ulcer is increasingly important.
Although not referring to diabetic foot ulcers when writing the above lines, the Scottish poet Thomas Campbell’s words can usefully be applied to the breakdown of the diabetic foot.
Ulceration does not occur spontaneously; rather, it is the combination of causative factors that result in the development of a lesion.
There are many warning signs or ‘shadows’ that can identify those at risk.
The famous Boston diabetes physician Elliot Joslin realised this over 70 years ago when, after observing many clinical cases of diabetic foot disease, he remarked ‘diabetic gangrene is not heaven-sent, but earth-born’.2 Thus, it is not an inevitable consequence of having diabetes that foot ulceration will eventually occur: ulcers invariably occur as a consequence of an interaction between specific pathologies in the lower limb and environmental hazards.
Those various pathologies that affect the feet and ultimately interact to increase vulnerability to ulceration will be considered in this chapter.
A clear understating of the aetiopathogenesis of ulceration is essential if we are to succeed in reducing the incidence of foot ulceration, and ultimately amputations.
Although some countries such as the Netherlands have achieved a reduction in diabetes-related lower limb amputations in recent years,3 this has not been a universal finding.
In Germany, for example, no change in the incidence of amputations could be observed in the 9 years until 2000.4 As the vast majority of amputations are preceded by foot ulcers,5 a thorough understanding of the causative pathways to ulceration is essential if we are to reduce the depressingly high incidences of ulceration and amputation.
Moreover, as lower limb complications are the commonest precipitants of hospitalisation of diabetic patients in most countries, there are potential economic benefits to be gained from preventative strategies, as noted in the previous chapters.
Potential economic savings of a successful amputation
The Foot in Diabetes, 4th Edition. Edited by Andrew J.M. Boulton, Peter R. Cavanagh and Gerry Rayman. C 2006 John Wiley & Sons, Ltd. ISBN: 0-470-01504-7
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52 THE PATHWAY TO ULCERATION
prevention programme were estimated to be between $2 million and $3 million over 3 years in a hypothetical cohort of 10 000 diabetic individuals.6 Finally, a successful screening programme based upon early identification of those at risk should impact on the appreciable morbidity, and even mortality, of diabetic foot disease, as emphasised by Krentz et al.7 The breakdown of the diabetic foot traditionally has been considered to result from an interaction of peripheral vascular disease (PVD), peripheral neuropathy and some form of trauma.
More recently, other contributory causes, such as psychosocial factors (Chapter 11) and abnormalities of pressures and loads under the foot,5 have been implicated.
The interaction between neuropathy and foot pressure abnormalities will be considered and, although covered in great detail in Chapter 21, the importance of vascular disease will be discussed briefly.
There is no compelling evidence that infection is a direct cause of ulceration: it is likely that infection becomes established once skin breaks occur, and so this topic will not be considered here.
Detailed discussion of infection can be found in Chapters 13 and 14.
PERIPHERAL VASCULAR DISEASE A number of large epidemiological studies have confirmed the frequency of all forms of ischaemic vascular disease in diabetes.8,9 The Diabetes Audit and Research in Tayside Scotland (DARTS) study from Scotland, for example, reported the annual incidence for the development of PVD in diabetic patients to be 5.5/1000 patients in those with type 1 diabetes, and 13.6/1000 in type 2 diabetes.9 In the US National Health and Nutrition Examinations Survey, 1999, 2000, the prevalence of PVD in the general population was 4.3%, but having diabetes was positively associated with prevalent PVD (odds ratio 2.83).10 PVD tends to occur at a younger age in diabetic patients and is more likely to involve distal vessels.
Reports from the United States and Finland have confirmed that PVD is a major contributory factor in the pathogenesis of foot ulceration and subsequent major amputations.11,12 In the assessment of PVD, simple clinical assessment of the distal circulation and non-invasive tests of the circulation by a hand-held Doppler ultrasound stethoscope can be useful in the assessment of outcome.8 In the pathogenesis of ulceration, PVD itself, in isolation, rarely causes ulceration: as will be discussed for neuropathy, it is the combination of risk factors with minor trauma that inevitably leads to ulceration (Figure 5.1).
Thus, minor injury and subsequent infection increase the demand for blood supply beyond the circulatory capacity, and ischaemic ulceration and the risk of amputation ensue.
Early identification of those at risk and education in good foot care habits are therefore potentially protective.
In recent years, neuroischaemic ulcers in which combination of neuropathy and PVD exists in the same patient, together with some form of trauma, are becoming increasingly common in diabetic foot clinics.
Whereas at the time of publication of the first edition of this volume (1987), neuropathic ulcers were most frequently seen in diabetic foot clinics, this has changed in the twenty-first century, with neuroischaemic ulcers now being the commonest in most clinics.
Although the United Kingdom Prospective Diabetes Study (UKPDS) suggested that tight control of blood glucose and blood pressure might influence the development of certain car- diovascular end points such as stroke and sudden death, statistical evidence that these influence the progression of PVD was not forthcoming.13,14 However, educational strategies aimed at the cessation of smoking and control of dyslipidaemia therefore remain of paramount importance.
Moreover, in view of the trends observed in the UKPDS, optimal glycaemic and blood pressure control should be aimed for.
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DIABETIC NEUROPATHY 53
Diabetes mellitus
Somatic sensory neuropathy Somatic motor neuropathy Autonomic neuropathy Peripheral vascular disease
Decreased pain, t° and Small muscle wasting Decreased sweating Altered blood flow proprioception
Dry skin Distended foot veins: Foot Deformities ‘warm feet’
Increased foot pressures Callus
Foot at risk
Repetitive trauma: e.g. ill-fitted shoes
Foot ulcer
Figure 5.1 Pathways to diabetic foot ulceration
DIABETIC NEUROPATHY As discussed in Chapter 3, the diabetic neuropathies represent the commonest of the long-term complications of diabetes, affect different parts of the nervous system and may present with diverse clinical manifestations.15 Most common among the neuropathies are chronic senso- rimotor distal symmetric polyneuropathy and the autonomic neuropathies.
It is the common chronic sensorimotor neuropathy and peripheral autonomic sympathetic neuropathy that to- gether play an important part in the pathogenesis of ulceration, and these will be discussed in some detail.
The association between peripheral neuropathy and foot ulceration has been recognised for many years: Pryce, a surgeon working in Nottingham over 120 years ago, re- marked that ‘it is abundantly clear to me that the actual cause of the perforating ulcer was a peripheral nerve degeneration’, and ‘diabetes itself may play an active part in the causation of the perforating ulcers’.
Sensorimotor Neuropathy Chronic sensorimotor neuropathy, which commonly occurs in both major types of diabetes, may be defined as ‘the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after exclusion of other causes’. The diagnosis cannot be made without a careful clinical examination of the lower limbs, as absence of symptoms can never be equated with absence of signs.16