Diabetic Foot Ulceration

The Pathway to Foot Ulceration

The risk factors for diabetic foot ulceration can be categorized into three distinct groups: pathophysiological, anatomic deformities, and environmental influences. The pathophysiological changes, which occur at the biomolecular level lead to changes that result in the development of peripheral sensory neuropathy, peripheral vascular disease, and a compromised immune system with alteration in wound healing capabilities. The second group with anatomic deformities are largely the result of motor neuropathy and in some cases Charcot neuroarthropathy. Finally, external or environmental influences in the form of acute or chronic trauma often precipitates the initiation of ulceration with initial soft tissue injury.

It is important to note that most of these risk factors do not act independently to produce foot ulceration. Instead, it is usually a combination of these risk factors that triggers a pathway leading to ulceration. Such risk factors can consist of a number of component causes, such as peripheral neuropathy, foot trauma, foot deformity, lower limb ischemia, foot edema, and callus formation. However, some risk factors seem to be more important in causing ulcerations. A critical triad of neuropathy, minor foot trauma, and foot deformity was found in more than 63% of foot ulcers in one study (27). As shown in Fig. 1, in the vast majority of diabetic foot ulceration, the first major component is the development of sensory neuropathy that causes pain insensitivity (11). The next component is the development of trauma, usually related to the high foot pressures that develop under the foot during walking. The trauma caused by the elevated foot pressures seen during normal walking are often the result of the changes in foot structure that occur as a result of the motor component of peripheral neuropathy. The third major component is the impaired wound healing, related to altered immune response, reduced blood supply at the wound area and abnormal expression of growth factors and other cytokines that are involved in the healing process. It is usually the combination of

Diabetic Foot Ulcer Process Formation

Fig. 1. The pathway to foot ulceration. Sensory neuropathy, associated with pain insensitiv-ity is the first component of the pathway. However, the development of ulceration also requires the existence of trauma, usually, related to the plantar tissue stress and injury that results from the development of high foot pressures during walking. The presence of the third component, impaired wound healing because of reduced blood flow in the ulcer area and aberrant expression of growth factors and cytokines, prevents the wound closure and leads to the development of chronic ulceration and, in some cases, amputation. (Modified from ref. 10.)

Fig. 1. The pathway to foot ulceration. Sensory neuropathy, associated with pain insensitiv-ity is the first component of the pathway. However, the development of ulceration also requires the existence of trauma, usually, related to the plantar tissue stress and injury that results from the development of high foot pressures during walking. The presence of the third component, impaired wound healing because of reduced blood flow in the ulcer area and aberrant expression of growth factors and cytokines, prevents the wound closure and leads to the development of chronic ulceration and, in some cases, amputation. (Modified from ref. 10.)

these three major components that lead to the development of chronic ulceration and amputation in cases where these progress to a limb or life threatening situation.

Peripheral Sensory Neuropathy

Reported in approximately 30-50% of all diabetic patients peripheral sensory neuropathy has been found to be the most common and sensitive predictor for foot ulceration in a patient with diabetes (28,29). In a study that specifically studied casual pathways of diabetic foot ulceration, the presence of neuropathy was reported in 78% of cases (27). The presence of peripheral sensory neuropathy initiates a series of events that eventually results in foot ulceration. A foot with impaired sensation provides little or no feedback to higher centers that cause a patient to continue to walk with little or no change in gait. This means that others with normal sensation would have the feedback to stop ambulating or at least alter their gait to allow the affected traumatized area to heal. With an inability to detect the pain signals that warn of impending tissue trauma, the insensate foot is exposed to continued increased pressures that hastens tissue damage leading to ulceration. This combination of increased forces coupled with impaired protective sensation are the key elements for ulcer genesis.

Ttt Wasting Distal Muscles Foot
Fig. 2. Changes related to motor neuropathy (minor foot). There is extensive wasting of the intrinsic muscles of the foot that results to clawing of the toes and prominence of the metatarsal heads.

Autonomic and Motor Neuropathy

Autonomic neuropathy is common in patients with long-standing diabetes. In the lower extremity, autonomic neuropathy might result arteriovenous shunting, resulting in the small arteries dilating (30). The resultant distension of the foot veins is not diminished even with foot elevation. Consequently, a neuropathic edema recalcitrant to diuretic therapy is observed. In addition to swelling, the neuropathic foot is also noted to be warm as a result of arterio-venous shunting (31). Autonomic neuropathy might decrease the activity of normally innervated skin appendages, such as sweat glands of the feet. The result is that the skin can become dry and less elastic. Dry, stiff skin cracks more easily forming splits or fissures notably around the heel rim and plantar medial aspect of the first metatarsophalangeal (MTP) especially during the dryer months. These cracks or fissures can become infected, resulting in a local cellulitis or they may even result in small longitudinal ulcerations that potentially can become infected (32).

Motor neuropathy in the foot causes weakness and wasting of the small intrinsic muscles, classically termed the "intrinsic minus" foot (Fig. 2). This leads to muscular imbalance with a characteristic clawing of the toes and plantarflexion of the metatarsal heads. Why? it seems that the intrinsic muscles of the foot act to stabilize and hold the phalanges of the toes straight as the long flexors and extensor tendons acting through their insertions into the distal phalanx pull the toes "up" into dorsiflexion as if "taking the foot off the gas pedal" or "down" into plantarflexion as if "stepping on the gas pedal." As the long flexors and extensors pull at the tips of the toes, the toes must be held straight and rigid. If the intrinsic muscles are unable to do this, the toes contract back into a hammertoe and ride up onto the metatarsal head forcing it into the weight-bearing surface with greater force. In addition, as the toes contract back into hammertoes, the fat pad plantar to the metatarsal heads shifts anteriorly. The soft tissue plantar to the metatarsophalangeal joints is not able to disperse the forces in this area as well as the plantar fat pad. Very often the atrophied intrinsics mean there is less bulk in the arch, which translates into less soft tissue bulk in the arch that is able to bear weight. The overall result of the changes in the foot because of motor neuropathy is a foot with a high arch, prominent metatarsal heads with very little plantar cushion, and hammertoes that are driving the metatarsal heads into the weight-bearing surface. The prominences at the plantar metatarsal head level and the digital level serve as areas of focal pressures with possible irritation from footwear. In the setting of sensory neuropathy, these areas of increased pressure brought about by the changes of motor neuropathy are at risk for ulceration.

Peak Plantar Pressures

Diabetic ulcers can occur on any part of the foot, but are clinically observed most frequently on the plantar surfaces. The predilection of diabetic foot ulcers to the plantar surfaces is related to the trauma that develops in these areas because of the increased peak plantar pressures during walking (33). Under normal conditions, the foot has the ability to distribute high forces that are applied on the plantar surface, especially on the ball of the foot, and therefore avoid the development of high foot pressures. This ability is greatly impaired in diabetes and is mainly because of the changes in the foot that are related to motor neuropathy that were described earlier and limited joint mobility (LJM) (see next section on joint mobility). As a result of this, the pressures under certain areas of the diabetic foot can be considerably high and lead to tissue injury even after walking short distances. As previously mentioned, in the presence of sensory neuropathy, the patient is unaware of warning signs of this injury, such as pain, and continues to walk until tissue integrity is compromised and foot ulceration occurs.

Numerous studies have shown that foot pressures are high in diabetic neuropathic patients (34-37). The high pressures tend to aggregate in the forefoot area or sites with bony prominence in the case of patients with Charcot neuroarthropathy. Usually, most ulcers develop under these areas of high foot pressures, but the development of ulceration in other foot areas can also occur. The development of high foot pressures starts in the early stages of diabetic neuropathy, even in the subclinical phase of the disease. One of the first steps is the transfer of high peak pressures from the heel area to the forefoot area, in the absence of any clinically detectable neuropathy (36). As neuropathy worsens and the clawing of the toes develops, there is further transfer of peak pressures from the toes to the forefoot area. In cases of severe neuropathy, the forefoot pressures are greatly elevated and the ratio between forefoot to rear foot pressures is increased as it would be expected. A forefoot to rearfoot ratio more than two was found to be more specific in identifying patients at risk for ulceration (38).

There are ample data to suggest that elevated foot pressures might predict a site of foot ulceration (34,35,39,40), but foot pressure measurements are characterized by a comparatively low sensitivity and are therefore not recommended as a primary screening tool

(33). Nonetheless, they do have a reasonable specificity and can be used in selected cases as a guide for the provision of proper foot wear that attenuates high pressures and therefore, decreases the risk of foot ulceration (41).

Limited Joint Mobility

Restriction of joint mobility is well documented in diabetes and is related mainly to collagen glycosylation that results in thickening of the periarticular structures, such as tendons, ligaments, and joint capsules (42,43). At the foot level, all joints might be involved though the subtalar and metatarsalphalangeal joints carry with them significant implications. The subtalar joint plays a major role in flattening of the arch or pronation. This is a shock absorbing mechanism of the foot, as the flattening of the arch reduces and attenuates ground reactive forces. LJM affecting the subtalar joint results in a foot that flattens out minimally or not at all. Consequently, LJM impairs the ability of the foot to adapt to the ground surface and absorb the shock that develops when the heel makes contact with the ground during walking. As a result of this, high foot pressures develop, mainly in the forefoot area, and are considered to be an additional factor in the development of foot ulceration (37,44-46). LJM also appears to vary along racial lines as compared with black patients, other patients have significantly less joint mobility (47).

Collagen glycosylation is also implicated in decreasing the resiliency of the Achilles tendon in patients with diabetes. Decreased motion of the Achilles tendon creates an equinus deformity with a further shift of plantar forces to the forefoot region (48). Surgical lengthening of the Achilles tendon has been found to effectively distribute plantar pressures more uniformly, decreasing the peak forces at the metatarsal region (49). But, surgical lengthening of the Achilles tendon does not restore plantar forefoot pressures to normal. This suggests that other structures may be involved to some extent. The plantar fascia itself might thicken and increase its resistance to tensile force rendering the arch of the foot less ability to undergo pronation (50). These results might further increase pressures under the metatarsal heads. The increased thickness of the plantar fascia also affects motion at the MTP's. It has attachments from the plantar aspect of the calcaneus to the base of the toes. If the plantar fascia becomes thick and tight, it then correlates with decreased motion of the MTP's as a closed plantar fascia will restrict motion of the toes. Therefore, gly-colsylation of collagen might also affect the mobility of the MTP's, which might increase pressures at sites related to motion of the MTP's. An example of this is the hallus interphalangeal joint (HIPJ), which is often the site of plantar ulcerations in cases of reduced mobility of the first MTP. When there is reduced dorsiflexion, i.e., reduced motion of pulling the great toe toward the knee, the HIPJ must hyperextend in terminal stance and a great deal of pressure is placed on the plantar aspect of the HIPJ predisposing to ulceration.

Peripheral Vascular Disease


Peripheral vascular disease is sometimes seen in patients with diabetes and pedal ulceration. It might be present in approximately 30% of cases (27). Impaired blood supply no doubt is a risk factor although not a major factor. It becomes a major factor after an ulceration has formed and becomes a major risk factor for amputation. Both micro-circulatory and macrocirculatory changes occur in patients with diabetes with peripheral vascular disease. Macrocirculatory disease in the patient with diabetes is identical to the atherosclerotic changes found in nondiabetics. Microcirculatory disease, on the other hand, is unique to the patient with diabetes.


Changes in the microcirculation in the foot of a patient with diabetes significantly impairs the ability of wound healing. Whereas, there are no occlusive lesions in the diabetic microcirculation, structural changes occur most notably by thickening of the basement membrane. However, this does not result in narrowing of the capillary lumen (51), but instead decreases the elastic properties of the capillary vessel walls and therefore, limits vasodilatation capacity. The basement membrane thickening might also impair the normal exchange of nutrients and cellular migration, decreasing the ability of the diabetic foot to fight infection (52). Despite these structural changes, it is the functional changes that are the most important. More specifically, during the last decade it has been realized that these changes are related mainly to the dysfunction of the endothelial cell and vascular smooth muscle cell of the arterioles, and the impairment of the nerve-axon reflex.

The single layer thick endothelium forms the luminal surface of all blood vessels. Normally, the endothelium synthesizes and releases vasoactive substances including vasodilators, such as nitric oxide, prostacyclin, and endothelium-derived hyperpolariz-ing factor and vasoconstrictors, such as endothelin, and prostaglandins that are vital in maintaining vascular tone and regulating blood flow (53). These vasomodulators primarily act at the vascular smooth muscle cells that are adjacent to the endothelial cells. The atherosclerotic changes seen in large vessels disease, such as monocyte migration or foam cell formation are not evident in those changes seen with the microcirculation. In addition, endothelial cells participate in angiogenesis, an important factor of the wound healing process.

Recent work during the last decade has shown that both the endothelium-dependent vasodilation and the independent one (that reflects the function of the vascular smooth muscle cell function) are impaired not only in diabetes, but also in the prediabetic stage as well (Fig. 3) (54). Furthermore, even in healthy subjects the microcirculation vasodilatory capacity at the foot level is reduced when it is compared with the forearm level. Thus, the additional reduction in vasodilation that is caused by diabetes can be critical for the skin and other foot tissues, as it restricts the maximal blood flow to levels that cannot sustain normal wound healing (55). Studies in our unit have shown that the endothelium-dependent vasodilation is equally impaired in diabetic neuropathic patients without large vessel disease and adequate arterial blood flow and in patients with obstructive arterial disease requiring bypass operation. The endothelium-dependent vasodilation was also impaired in both groups, but was more pronounced in patients with large vessel disease (56,57).

Another important factor that affects the neuropathic foot microcirculation is the impairment of the nerve-axon reflex. Under normal conditions, stimulation of the C-nociceptive fibers leads to retrograde stimulation of adjacent fibers, which secrete a number of vasomodulators, such as substance P, calcitonin gene related peptide (GCRP), histamine, and so on, that produce vasodilation (also known as Lewis triple flare

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  • almaz
    Why diabetic ulcer is seen in foot mainly?
    6 years ago

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