Aetiology

Various factors increase the risk of developing a diabetic foot ulcer.[14] These factors fall into three main categories:

  • Abnormal distribution of plantar pressures due to structural/biomechanical abnormalities (e.g., bunions, hammer or mallet toes, midfoot deformities as a result of Charcot neuro-osteoarthropathy), impaired joint mobility, gait abnormalities, and motor neuropathies

  • Impaired protective mechanisms (e.g., dry skin, immune system abnormalities, peripheral artery disease)

  • Impaired recognition due to sensory neuropathy and/or visual impairments.

In most patients, epithelial ulceration results from repetitive trauma from the shoe contacting various prominent skin surfaces of the foot during ambulation. This, in addition to various combinations of the above factors, leads to a portal of entry for bacterial inoculation into the foot. Moreover, puncture wounds, along with these various risk factors, may also lead to bacterial inoculation and subsequent infection.

Pathophysiology

A healthy, intact visco-elastic and supple epithelium is the most important protection against foot infection. When various combinations of risk factors are present, ulceration or puncture injuries occur. The longer the duration of a wound, the higher the risk of both soft-tissue and bone infection. Infection often spreads along anatomical planes in the foot and will often cause hyperglycaemia. Chronic hyperglycaemia may lead to sensory neuropathy and immune system dysfunction, but hyperglycaemia does not directly affect the development of foot infections.

Untreated macrovascular atherosclerotic disease (typically popliteal- and tibial-level) poses a higher risk for foot infections among those with unhealed foot ulcers and increases the risk for amputation.[15][16] Although microvascular abnormalities (including abnormal arteriovenous shunting and basement membrane thickening) are often present in patients with diabetes mellitus, there has been no evidence that occlusive phenomena in the microvasculature of the foot (i.e., small-vessel disease) contributes significantly to ulcer development, infection, or poor healing. Indeed, it was pointed out decades ago that a belief in the concept of small-vessel disease often leads to inappropriate pessimism towards the treatment of diabetic foot infections.[17]

There is significant overlap between risk factors for macro- and microvascular disease in diabetes-related foot disease, but in general hypercholesterolaemia and hypertension are more often associated with macrovascular disease development, whereas hyperglycaemia is most often associated with microvascular disease.[18] Many cardiovascular risk factors, such as tobacco use, are strongly associated with worsening of both macro- and microvascular disease, and both processes contribute to non-healing of diabetic foot ulcers. Cellular dysfunction is also thought to play a significant role in delayed wound healing, in particular dysregulation of immune cells causing chronic inflammation, and damage to endothelial and smooth muscle cells which impairs angiogenesis.[18]

The pathophysiological factors contributing to diabetes-related foot disease can be further compounded by societal and ethnic health disparities: US studies have found higher amputation rates among communities with economic hardship and rural-dwelling populations, and among Black and African-American, Hispanic and Latino, and Native American populations.[18] In the UK, by contrast, studies have found lower amputation rates in African and Caribbean men and in people of South Asian origin, compared to other ethnic groups, suggesting these discrepancies are driven more by socio-economic and regional variations than genetic factors.[19][20]

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