Diabetic foot pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Anahita Deylamsalehi, M.D.[2]Vishnu Vardhan Serla M.B.B.S. [3]

Overview

Diabetic foot is an umbrella term for foot problems in patients with diabetes mellitus. Neuropathy, ischemia and trauma are three main pathogenesis of diabetic foot. Neuropathy is the most common and is the responsible element in more than 60% of diabetic foot cases. Factors such as high blood glucose, reactive oxygen species, insufficient oxygenation of the nerves, and inflammation leads to neuropathy development in diabetic patients and it gets worse with alcohol use and smoking. Neuropathy can involve motor, autonomic, or sensory nerves and is able to involve both large and small fibers. Motor nerve involvement can lead to some mechanical changes in the foot of a diabetic patient, which causes more plantar pressure and higher risk of callus formation. Each and every factor leads to a higher rate of skin breakdown and ulceration. Autonomic neuropathy leads to anhidrosis and impaired function of oil glands, subsequent skin dryness, higher chance of skin breakdown, and ulcer formation. Diabetic patients with sensory neuropathy are more prone to ulcer formation and related complications, since they don't feel pain with ever-deepening ulcers. Ischemia is the second best known pathogenesis of diabetic foot that could occur due to a higher rate of lower limb atherosclerosis in diabetic patients, compared to the normal population. Diabetes related complications such as micro and macrovascular complications further intensify ischemia. Ischemic changes can be discovered by an impaired ankle brachial index (ABI). Trauma to the foot usually acts as a trigger for diabetic foot. A defective hypoxic response has been explained in diabetic foot, which is related to a transcription factor named hypoxia‐inducible factor‐1 (HIF‐1). Lower levels of HIF‐1 in biopsies of diabetic foot could be related to its role in wound healing. Some genetic associations (such as MAPK14 gene located on chromosome 6, decreased expression of certain cytokines and growth factors, and the HSPA1B genotype) have been explained in diabetic foot development. Charcot arthropathy, some psychosocial conditions, necrotizing fasciitis (NF), vitamin D deficiency, tinea pedis, onychomycosis, and diabetic retinopathy are associated conditions in diabetic foot. On gross pathology, the most common site of ulceration is on the soles of the feet, under the metatarsal head with various depths and possible anatomical deformities of the foot. In microscopic evaluations of the ulcers, evidence of necrosis, hyperkeratosis, fibrosis, inflammation, cellular debris, granulation tissue, and angiogenesis have been found.

Pathophysiology

• Diabetic foot is an umbrella term for foot problems in patients with diabetes mellitus. There are numerous responsible pathogenesis, such as arterial abnormalities, diabetic neuropathy, delayed wound healing, and being more vulnerable to infection or gangrene of the foot. The key components of diabetic foot are neuropathy, ischemia, and trauma.
• Only 10% of diabetic foot cases are exclusively due to ischemia, nevertheless, 90% of them are related to neuropathy (alone or in combination to ischemia).
• Components such as neuropathy and peripheral arterial disease can mask signs and symptoms of the local infection.
• Based on a study done on diabetic patients with foot ulcers, three components such as peripheral neuropathy, deformity, and trauma were responsible for pathogenesis of diabetic foot in 63% of cases.

Neuropathy

• The most important cause of diabetic foot is neuropathy. Based on a study, more than 60% of cases of diabetic foot are due to neuropathy.
• It involves roughly more than half of the patients with diabetes who are older than 60 years old.
• Peripheral neuropathy is usually profound at the point where it leads to the formation of a foot ulcer.
• Some metabolic abnormalities are due to hyperglycemia which leads to ischemia of endoneurial microvessels. In a nutshell, these changes are most likely caused by a combination of the factors listed below:
  • High blood glucose
  • Reactive oxygen species
  • Vasculopathy
  • Insufficient oxygenation of the nerves
  • Presence of inflammation and autoimmunity due to diabetes
  • Genetic factors
  • Mechanical injury
  • Smoking
  • Alcohol abuse
• Generalized symmetric distal polyneuropathy is the most common and widely recognized form of diabetic neuropathy that leads to diabetic foot. It may be either motor, autonomic, or sensory, and can involve small fibers, large fibers, or both.
  • Motor nerve involvement:
    • Motor nerve involvement can lead to some mechanical changes in the foot of a diabetic patient due to loss of sufficient neural supply and alteration in the natural anatomy of the foot. These mechanical changes cause more plantar pressure and a higher risk of callus formation, which subsequently leads to a higher rate of skin breakdown.
    • Moreover, these anatomical changes usually result in wider and thicker feet, which no longer fit in the patient's regular shoes and cause more trauma.
    • Pathogenesis of some of these mechanical changes are listed below:
      • Deprivation of neural supply to the intrinsic muscles of the foot → Long flexor and extensor tendons imbalanced → Flexion of the foot → High-arched foot and claw-toe deformity
      • Toes hyperextension → Overriding of the metatarsal-phalangeal joints and downward displacement of metatarsal heads → Increased prominence of both
      • Toes hyperextension → Distal displacement of metatarsal fat pads → Altering the natural cushioning of these fat pads
  • Autonomic neuropathy:
    • Autonomic neuropathy leads to anhidrosis and impaired function of oil glands. The subsequent dryness of the skin results in a higher chance of skin breakdown, ulcer formation, and bacterial invasion.
    • Autonomic neuropathy also decreases the proper peripheral sympathetic vascular tone which can lead to higher blood flow and pressure in distal arteries. The aforementioned changes plus capillary basement membrane destruction leads to edema. Edema itself increases the risk of ulcer formation.
  • Sensory neuropathy:
    • Appropriate sensory system helps patients to notice the tiniest fissures or blisters on their skin. This early sensation makes it possible for patients to take care of these skin defects and prevent further complications.
    • Conversely, diabetic patients with sensory neuropathy are more prone to ulcer formation and related complications, since they don't feel pain with their ever-deepening ulcers.

Ischemia

• Atherosclerosis:
  • Atherosclerosis of the lower limb is 2 to 3 times more common in diabetic patients, compared to the normal population.
  • Investigators reported that atherosclerosis in diabetic patients is more prominent in tibial and fibular arteries of the calf, and arteries of the foot are relatively spared.
  • It usually occurs due to inflammation and consequently leads to accumulation of the foam cells.
• Micro and macrovascular complications are one of the leading causes of diabetic complications. Microvascular complications cause skin damage, infection, and impaired wound healing.
• The vascular changes which are responsible for foot problems include stiff arteries due to calcification of the smooth muscle cells in the arterial wall (mediasclerosis). Consequently, the stiff arteries are unable to expand in response to systolic pressure, which can lead to the movement of plaques in calf arteries.
• Most of these changes are discovered by an impaired ankle brachial index (ABI).
  • The resting ABI is the ratio of the blood pressure in the lower limb to the blood pressure of the arms. It is calculated by dividing the systolic blood pressure of the ankle by the systolic blood pressure of the arm.
  • It is a non-invasive method to assess the lower extremty arterial system and to detect the presence of arterial occlusion disease.
• Even in the presence of neuropathic foot ulcers, the reason of non healing wounds could be due to impaired blood supply to the tissue, which could be further augmented by antihypertensive medications..

Trauma

• Trauma to the foot is frequently the trigger of diabetic foot ulcer development, and repetitive trauma and pressure to the area prevent healing.
• Excessive plantar pressure is related to limited joint mobility and foot deformities (such as charcot foot and hammer toe). Limited joint mobility and abnormal foot biomechanisms have been associated to an increased risk of ulceration.
• Poor vision and sensory neuropathy further put diabetic patients at risk of foot ulceration, as they do not feel the pain, nor do they see the ulcer. Loss of balance can also make patients more susceptible to falls.

Defective hypoxic response

• A transcription factor named hypoxia‐inducible factor‐1 (HIF‐1), which becomes stable in hypoxia, functions as a oxygen homeostasis regulator.
• Since HIF‐1 helps cells to respond adequately to hypoxia (by regulating erythropoiesis, metabolic changes, angiogenesis, proliferation, migration, and cell survival), it plays a critical role in wound healing.
• In addition, hypoxia‐inducible factor‐1 is responsible for the expression of genes that are critical to facilitate wound healing, such as the GLUT1 and GLUT3, lactate dehydrogenase, genes responsible for proper mitochondrial function (such as phosphoinositide‐dependent kinase‐1), type I collagen, and fibronectin.
• There are numerous studies that detected lower levels of HIF‐1 in biopsies of diabetic foot.
• One of the known pathogenesis of destabilized hypoxia‐inducible factor‐1 is hyperglycemia. This destabilization in hyperglycaemic conditions has been explained by an increase in the tendency of HIF‐1 towards VHL‐dependent degradation.

Genetics

• Naturally growth factors and cytokines are two mediators involved in wound healing. It is crystal clear that any genetical changes that affect the aforementioned mediators can result in defective wound healing and higher chance of diabetic foot. The following are some known genetical changes:
  • A single nucleotide polymorphism (SNPs) is responsible in the variation of these growth factors and cytokines. The best known gene is MAPK14 located on chromosome 6.
  • Decreased expression of certain cytokines and growth factors (such as IGF-1, TGF‐β1, PDGF, EGF, Interleukin 8, and Angiopoietin‐2)
• The HSPA1B genotype, a member of the heat shock protein 70 (Hsp70) family, has been related to a higher chance of diabetic foot development, amputation, and elongated hospital stay.

Associated Conditions

Conditions associated with diabetic foot include:

• Charcot arthropathy
• Peripheral arterial disease
• Psychosocial conditions, such as depression
• Necrotizing fasciitis (NF)
• Vitamin D deficiency
• Fungal infections, such as tinea pedis and onychomycosis
• Other complications of diabetes mellitus, such as diabetic retinopathy and nephropathy
• Hypertension

Gross Pathology

Diabetic foot ulcer, source:wikimedia commons

Charcot joint, source:wikimedia commons

• On gross pathology, the most common site of ulceration is on the soles of the feet, under the metatarsal head (particularly at the second metatarsal head).
• Depth of ulcers could be different, ranging from superficial wounds to the involvement of ligaments and tendons, joint capsule, or deep fascia
• There is a high chance of concurrent anatomical foot deformities, such as claw toe or charcot joint.
• Presence of infective features of a ulcer, such as erythema, swelling, and purulent and malodor discharge.
• Abscess
• Gangrene

Microscopic Pathology

The following list is a summary of the possible microscopic histopathological changes of diabetic foot:

• Skin necrosis
• Hyperkeratosis
• Fibrosis
• Inflammation
• Cellular debris
• Granulation tissue
• Biofilms formation, which resembles infection
• Angiogenesis, which represents proper wound healing