What is the pathophysiology and manifestation of diabetic foot ulcers?

Pathophysiology of Diabetic Foot Ulcers

Diabetic foot ulcers develop through a triad of peripheral neuropathy, peripheral arterial disease, and trauma, with neuropathy being the central pathophysiological mechanism that leads to an insensitive and deformed foot vulnerable to unnoticed injury. 1

Primary Pathophysiological Mechanisms

Peripheral Neuropathy (Central Driver)

Diabetic peripheral neuropathy is the cornerstone pathophysiological mechanism, manifesting in three distinct forms that collectively create vulnerability to ulceration 1:

• Sensory neuropathy causes loss of protective sensation, allowing minor trauma to go unnoticed and precipitating ulceration 1
• Motor neuropathy produces foot deformities including claw toes and hammer toes, creating areas of high pressure that are prone to breakdown 1
• Autonomic neuropathy reduces sweating, leading to dry skin that is prone to cracking and serves as an entry point for infection 1

Biomechanical Cascade

The neuropathic foot undergoes a predictable pathological sequence 1, 2:

• Loss of sensation combined with foot deformities results in abnormal walking patterns and biomechanical loading of the foot 1
• High pressure areas develop, to which the body responds with thickened skin (callus formation) 1
• Callus formation paradoxically increases abnormal loading, often leading to subcutaneous hemorrhage visible as brown discoloration 1, 2
• Continued pressure causes tissue breakdown beneath the callus, eventually leading to ulceration 1

Peripheral Arterial Disease

PAD is present in approximately 50% of patients with diabetic foot ulcers and acts as a critical cofactor 1:

• Accelerated atherosclerosis in diabetes predominantly affects the infra-inguinal vasculature, particularly the popliteal artery and vessels of the lower leg 3, 2
• Calcification of the media layer of vessels (medial arterial sclerosis) is a hallmark of diabetic peripheral vascular disease 2
• PAD severely impairs wound healing and dramatically increases the risk of lower extremity amputation 1
• The combination of infection with PAD is associated with markedly increased risk of poor healing and represents a limb-threatening emergency 1

Infection Pathophysiology

Infections follow a predictable progression once the protective skin barrier is breached 1, 4:

• Infections begin with a break in the protective cutaneous envelope, typically at a site of trauma or ulceration 1
• Open wounds become colonized with skin flora and ultimately infected 1
• Microorganisms spread contiguously to subcutaneous tissues, including fascia, tendons, muscles, joints, and bones 1
• Acute infections in antibiotic-naïve patients are usually monomicrobial with aerobic gram-positive cocci, while chronic wounds develop complex polymicrobial flora 4

Contributing Metabolic and Immunological Factors

Several systemic factors amplify the pathophysiological cascade 1:

• Poor glycemic control predisposes to infection and impairs wound healing 1
• Diabetes-related immunological perturbations, particularly neutrophil dysfunction, contribute to poor wound healing 1
• Chronic renal failure increases risk of foot infection 1

Clinical Manifestations

Ulcer Characteristics

Diabetic foot ulcers typically present with specific features 3, 5:

• Location: Approximately 93% occur on the foot, with the remaining 7% on the ankle or leg, usually at sites of high pressure on the plantar aspect 3, 5
• Depth: Most extend into subcutaneous tissue or beyond (Stages III and IV of the International Association of Enterostomal Therapy classification) 6
• Size: 95% of ulcers measure up to 10 cm² in area 6

Vascular Manifestations

Ischemic changes present distinctively in diabetic patients 2:

• Dependent rubor: Reddish-brown discoloration when the foot is dependent, indicating severe peripheral ischemia 2
• Pallor on elevation of the affected limb 2
• Absence of hair growth and dystrophic toenails 2
• Brown discoloration may represent either subcutaneous hemorrhage from repetitive stress or dependent rubor from critical ischemia 2

Neuropathic Manifestations

The insensate foot demonstrates characteristic findings 1:

• Loss of protective sensation allowing painless progression of ulceration 1
• Foot deformities creating visible areas of abnormal pressure distribution 1
• Dry, cracked skin from autonomic dysfunction 1

Critical Clinical Pitfalls

Do not assume brown discoloration is benign pigmentation—it often represents either subcutaneous hemorrhage from repetitive stress or dependent rubor from critical ischemia 2:

• Brown discoloration with absent pedal pulses and dependent rubor requires urgent vascular imaging and consideration for revascularization 2
• Patients with peripheral neuropathy may have atypical or absent symptoms despite severe ischemia causing tissue discoloration 2
• An ankle-brachial index (ABI) >1.3 does not rule out vascular disease—it indicates poorly compressible vessels from arterial wall calcification, requiring alternative vascular assessment such as toe pressures or transcutaneous oxygen pressure 2
• Patients with signs of PAD and a foot infection are at particularly high risk for major limb amputation and require emergency treatment 3