Diabetic foot

Diabetic foot is a complex clinical syndrome in which chronic damage caused by diabetes mellitus to peripheral nerves, the tissue microenvironment, the immune response, and the arterial circulation of the lower limbs promotes ulceration, deep infection, osteomyelitis, Charcot neuroarthropathy, and, in the most advanced cases, gangrene and amputation. It therefore does not coincide solely with the presence of an ulcer, but encompasses the entire spectrum of pathological conditions that make a patient's foot vulnerable to trauma, unable to recognize it promptly, and often unable to heal within an appropriate time. The most typical clinical presentation is an ulcer below the malleoli in a foot with loss of protective sensation, biomechanical deformities, hyperkeratosis, variable ischemia, and a high risk of infection.

From an epidemiological standpoint, diabetic foot is one of the most burdensome chronic complications of diabetes because of its frequency, healthcare costs, loss of independence, and prognostic impact. During their lifetime, a very substantial proportion of people with diabetes develop a foot ulcer and, once healed, recurrence is extremely common. The problem is not merely local: a foot ulcer is a marker of advanced systemic disease because it is often associated with severe neuropathy, peripheral artery disease, chronic kidney disease, cardiovascular frailty, and increased mortality. Diabetic foot should therefore not be interpreted as an isolated skin lesion, but as the peripheral expression of complicated diabetes requiring comprehensive, rapid, and multidisciplinary care.

The clinical burden of the syndrome is also enormous because many nontraumatic lower-limb amputations are preceded by an ulcer, and progression to major adverse outcomes is promoted by diagnostic delays, inappropriate footwear, failure to offload plantar pressure, underestimation of ischemia, inappropriate antibiotic use, delayed recognition of osteomyelitis, and inadequate organization of specialist pathways. Prognosis changes radically when the patient enters an integrated system early, bringing together diabetology, podiatry, vascular surgery, infectious diseases, orthopedics, radiology, and wound care. This dependence on timeliness and pathway quality makes diabetic foot a paradigmatic multidisciplinary condition.

The underlying etiological event is chronic exposure to hyperglycemia, which triggers a cascade of metabolic and neurovascular abnormalities responsible for peripheral tissue damage. However, diabetic foot does not arise from a single elementary lesion, but from the interaction of several pathogenic components that reinforce one another. The first is diabetic peripheral neuropathy, particularly its distal symmetric sensorimotor and autonomic form. The second is peripheral artery disease, which is often multisegmental and particularly involves the tibial and infrapopliteal territories. The third is susceptibility to infection, promoted by innate and adaptive immune abnormalities, reduced perfusion, delayed diagnosis, and persistence of necrotic tissue. Around these three pillars act aggravating factors such as foot deformity, limited joint mobility, callus formation, previous ulceration, previous amputations, chronic nephropathy, visual impairment, reduced ability for self-care, poor access to care, and traumatic footwear.

Sensory neuropathy causes loss of protective sensation, meaning the inability to perceive pain, heat, pressure, and repeated minor trauma. Under normal conditions, pain forces a person to alter their gait, stop the activity, or change footwear; in a patient with neuropathy this warning system is lost, and the person continues walking on an area of mechanical overload until damage becomes evident. Motor neuropathy disrupts the balance between the intrinsic and extrinsic muscles of the foot, promoting hammer toes, prominence of the metatarsal heads, changes in the plantar arches, and abnormal pressure distribution. Autonomic neuropathy reduces sweating, causes dry and fissured skin, alters vasomotor function, and facilitates breakdown of the skin barrier. A neuropathic plantar ulcer therefore usually arises not from a single acute trauma, but from repetitive microtrauma to an insensate and biomechanically deformed foot.

Hyperkeratosis plays a central role. A callus is not an innocuous finding, but a sign of an area exposed to chronic excessive pressure. Keratin accumulation further increases focal pressure, acts as a hard body interposed between the ground and deeper tissues, and promotes subcallous hemorrhage, tissue necrosis, and subsequent ulceration. The classic pathogenic sequence of a neuropathic lesion is therefore pressure overload, callus formation, subcallous hemorrhage, necrosis, fissuring or skin breakdown, and ulcer formation. If the patient continues walking without offloading, healing becomes unlikely even with a technically appropriate dressing, because every step mechanically reopens the wound bed.

Peripheral artery disease profoundly changes this scenario. In patients with diabetes, foot ischemia is often distal, complex, and associated with medial arterial calcification, which makes some traditional hemodynamic tests less reliable when interpreted in isolation. Reduced perfusion limits the delivery of oxygen, nutrients, immune cells, and antibiotics to infected or ulcerated tissues; slows granulation; impairs re-epithelialization; and promotes progression to necrosis and gangrene. It is important to emphasize that so-called diabetic microangiopathy should not be considered the primary cause of ulceration or failure to heal before true peripheral artery disease has been excluded. Many ulcers generically labeled “vascular” are actually neuroischemic, because neuropathy and ischemia frequently coexist in the same foot. This explains why an ischemic ulcer may be surprisingly painless in a person with diabetes: neuropathy masks the traditional symptoms of ischemia.

The infectious component develops in tissue that is already biologically compromised. Chronic hyperglycemia impairs leukocyte function, chemotaxis, phagocytosis, and some microbicidal mechanisms; necrosis, exudate, and devitalized tissue create a microenvironment favorable to bacterial proliferation; and reduced perfusion limits antibiotic penetration and the host's ability to contain the process. A diabetic foot infection is not merely superficial colonization, but an anatomical progression that can rapidly extend into subcutaneous tissue, fascia, tendons, joints, and bone. Progression to osteomyelitis is particularly likely when the ulcer is deep, chronic, located over a bony prominence, or associated with exposed bone or bone that is easily reached on probing. In this context, distinguishing bacterial colonization from clinically relevant infection is essential, because indiscriminate antibiotic use does not sterilize the ulcer bed and selects for resistance without correcting the underlying biomechanical or ischemic problem.

Charcot neuroarthropathy deserves separate mention because it falls fully within the diabetic foot spectrum. Sensory and autonomic neuropathy combine with repeated unperceived trauma and an abnormal osseous inflammatory response capable of causing osteolysis, fragmentation, subluxation, and architectural collapse of the foot. In the early stages, the skin may be intact, but the foot appears warm, edematous, and erythematous; if diagnosis is delayed and weight-bearing continues, the deformity becomes structural and creates new areas of excessive plantar pressure, with recurrent ulcers over bony prominences. Charcot neuroarthropathy is therefore not merely an osseous complication of diabetes, but one of the mechanisms that transforms a neuropathic foot into a chronically ulcerated foot at extremely high risk of amputation.

This results in an integrated pathophysiology in which chronic diabetes causes neuropathy, ischemia, immune dysfunction, and tissue fragility; these abnormalities promote unperceived trauma, skin breakdown, and ulceration; the ulcer becomes an entry point for infection; infection deepens tissue destruction and may extend to bone; ischemia prevents repair and reduces treatment efficacy; biomechanical deformity perpetuates overload; and recurrence remains likely even after apparent healing. This sequence explains why diabetic foot must be addressed simultaneously as a neurological, vascular, biomechanical, infectious, and organizational problem.

The clinical presentation of diabetic foot depends on the relative contributions of neuropathy, ischemia, infection, and deformity, but the medical history often provides early direction. The patient may report long-standing poorly controlled diabetes, previous neuropathy, prior ulcers, minor amputations, visual difficulties, chronic nephropathy, or use of rigid, unsuitable footwear. In predominantly neuropathic forms, pain may be absent or surprisingly mild despite a substantial lesion; some patients report noticing the wound only because of a blood stain on the sock, a foul odor, or because a family member saw it. Others describe paresthesias, burning, the sensation of walking on cotton, or loss of hot and cold perception, indicating already advanced sensory damage.

Physical examination begins with general inspection of the limb and footwear. A typical neuropathic foot is warm and relatively well perfused, with dry skin, fissures, calluses, and deformities of the toes or forefoot; the ulcer is often plantar, surrounded by hyperkeratosis, and located beneath the metatarsal heads, at the heel, or at other weight-bearing points. By contrast, an ischemic foot tends to be colder, pale or cyanotic, with thin atrophic skin, hair loss, dystrophic nails, and diminished or absent pulses; lesions are more likely along the margins of the foot, on the toe pads, in periungual regions, or on lateral surfaces exposed to friction. In practice, however, many patients have a neuroischemic foot, in which lesion location, limited pain, and trophic signs overlap and make the presentation less schematic.

When infection develops, the clinical picture can change rapidly. The ulcer may become deeper, exudative, and malodorous, with periwound erythema, edema, increased temperature, fluctuant soft tissue, purulent discharge, or necrotic areas. Pain may appear or increase, but its absence does not exclude severe infection in a patient with neuropathy. Advanced cases may present with fever, chills, tachycardia, hypotension, marked hyperglycemia, or sudden deterioration of metabolic control. At times, the first manifestation of a deep collection is a small skin opening with extensive underlying destruction, particularly in infections of the plantar compartments. Visible or palpable bone at the base of the lesion, a long-standing ulcer, and failure to respond to care strongly suggest osseous involvement.

Active Charcot neuroarthropathy has a distinctive clinical presentation and is often mistaken for cellulitis, gout, venous thrombosis, or a simple injury. The patient presents with a red, swollen foot or ankle that is warmer than the contralateral side, with initially intact skin and little or no pain. The temperature asymmetry may be striking, and the history often includes minimal trauma or no recognized trauma at all. If it is not suspected immediately and the patient continues weight-bearing, joint instability, midfoot collapse, and a convex plantar deformity—the so-called “rocker-bottom” foot—develop progressively, followed by ulcers over bony prominences. Failure to identify Charcot neuroarthropathy early is one of the most harmful clinical errors in diabetic foot care.

In addition to any active lesion, signs of a high-risk foot must always be sought: marked hyperkeratosis, subcallous hemorrhage, rigid deformities, limited joint mobility, hallux valgus, hammer toes, pes cavus, previous scar sites, sequelae of amputation, interdigital fungal infection, ingrown toenails, poor hygiene, maceration, chronic edema, and abnormalities inside the footwear. These findings are not secondary details, but intermediate steps in the natural history of the disease. Patients do not suddenly develop a diabetic foot ulcer; they reach it through a sequence of minor clinical signs that, if interpreted in time, permit primary or secondary prevention.

Finally, the clinical impact is not only local. Many patients simultaneously experience functional limitation, reduced walking, fear of weight-bearing, social isolation, insomnia, neuropathic pain, loss of independence in daily life, and impaired quality of life. The mere presence of an ulcer changes the patient's entire clinical trajectory because it increases hospital visits, the risk of sepsis, the need for vascular or surgical procedures, and the probability of medium-term death. Proper clinical assessment must therefore always combine examination of the foot with evaluation of the person as a whole.

The diagnostic workup for diabetic foot must follow a precise logic, because the most common error is to focus on wound dressing before determining whether the dominant problem is neuropathic, ischemic, infectious, osteoarticular, or mixed. The first level is always clinical and includes a structured history, complete inspection of both feet, assessment of footwear, identification of deformities, definition of lesion location and depth, palpation of peripheral pulses, neurological examination for protective sensation, and identification of signs of infection or active Charcot neuroarthropathy. Loss of protective sensation should not be inferred impressionistically: it is documented using a 10-g monofilament, ideally combined with at least one other test such as a 128-Hz tuning fork, gentle pinprick, or thermal sensation testing, to define the neurological deficit more robustly.

According to the International Working Group on the Diabetic Foot (IWGDF) guidelines, proper assessment of an active diabetic foot requires:

• determining whether loss of protective sensation is present using standardized neurological tests;
• always assessing for peripheral artery disease through history, physical examination, pulse palpation, and appropriate noninvasive vascular tests;
• determining whether the lesion is infected on clinical grounds, without confusing colonization with infection;
• classifying the ulcer with a shared system, preferably SINBAD for clinical communication, and considering WIfI when estimating amputation risk and the potential benefit of revascularization;
• excluding or confirming osteomyelitis and Charcot neuroarthropathy when clinical findings suggest them;
• promptly identifying patients who require an urgent multidisciplinary pathway, vascular imaging, infection-related surgery, or vascular surgery.

Ulcer classification is an essential practical step. The SINBAD system considers Site, Ischemia, Neuropathy, Bacterial infection, Area, and Depth, allowing a concise but clinically useful description of the lesion and facilitating comparison among centers. When limb threat is substantial, particularly in the presence of peripheral artery disease, the WIfI system—Wound, Ischemia, and foot Infection—provides a more sophisticated stratification of amputation risk and the likelihood that the patient will benefit from revascularization. For infection, the PEDIS classification and IWGDF/IDSA framework distinguish uninfected, mild, moderate, and severe forms, guiding antibiotic intensity, the need for hospitalization, and the urgency of surgical treatment.

The diagnosis of diabetic foot infection is clinical. A positive culture or the presence of superficial bacteria in the ulcer bed is not sufficient, because almost all chronic ulcers are colonized. Infection requires compatible local or systemic signs such as erythema, warmth, edema, pain, purulent exudate, friable tissue, foul odor, extension into deep planes, or sudden deterioration of the lesion. When infection is suspected, the best microbiological specimen is not a superficial swab taken from a contaminated wound bed, but a deep-tissue sample obtained after cleansing and debridement, or a bone sample when osteomyelitis is suspected. This point is crucial: poorly performed microbiological sampling readily leads to inappropriate antibiotics, excessively broad or unnecessary treatment, and delayed control of the true infectious focus.

Osteomyelitis should be suspected in deep, chronic, large ulcers located over bony prominences, with exposed bone or bone easily reached by the probe-to-bone test. Diagnosis is not based on a single test, but on a reasoned combination of clinical findings, plain radiography, inflammatory markers, and advanced imaging. Foot radiography is a mandatory initial examination because it may reveal foreign bodies, soft-tissue gas, deformities, bone lysis, periosteal reaction, subluxations, or signs of Charcot neuroarthropathy; however, it may still be normal in the early stages. If uncertainty remains, magnetic resonance imaging is the test of choice for defining the extent of soft-tissue and bone involvement, identifying abscesses, sinus tracts, and osteomyelitis, and supporting differentiation from Charcot neuroarthropathy. In selected cases, particularly when the treatment decision depends on precise microbiological identification, an aseptically obtained percutaneous or intraoperative bone specimen provides the strongest reference for etiological diagnosis.

Vascular assessment cannot be superficial. A palpable pulse does not completely exclude significant arterial disease, and an apparently normal ankle-brachial index may be falsely reassuring because of medial arterial calcification. Hemodynamic diagnosis therefore requires integration of pulse palpation, continuous-wave Doppler waveform analysis, the ankle-brachial index, toe-brachial index, toe pressure, and, when necessary, transcutaneous oxygen pressure measurement. In an ulcerated foot, perfusion data are used not only to establish whether peripheral artery disease exists, but also to estimate the probability of healing and determine when urgent vascular surgical involvement is needed. Markedly reduced ankle, toe, or transcutaneous oxygen pressures, monophasic or absent Doppler waveforms, failure of ulcer area to decrease despite appropriate care, gangrene, or infection associated with ischemia require acceleration toward arterial imaging and possible revascularization.

Active Charcot neuroarthropathy requires a specific diagnostic approach. It should be considered from the outset in every person with diabetes and neuropathy who presents with a swollen, warm, red foot with intact skin. The temperature difference from the contralateral side can be documented with infrared thermometry, while plain radiography can identify fractures, fragmentation, subluxations, and osseous collapse if the process is already advanced. If radiographs are negative but clinical suspicion persists, magnetic resonance imaging can detect bone marrow edema and early osteoarticular abnormalities. It is important to remember that normal inflammatory markers do not exclude Charcot neuroarthropathy when the skin is intact, and that the greatest delay arises from relying too heavily on laboratory tests and too little on physical signs.

Once the active condition has been defined, the patient must also be placed in a future-risk perspective. The IWGDF guidelines stratify ulcer risk according to loss of protective sensation, peripheral artery disease, deformity, history of ulcer or amputation, and advanced kidney failure. This stratification is not academic: it determines follow-up intensity, frequency of preventive visits, need for therapeutic footwear, requirement for reinforced education, and the threshold for rapid access to specialist centers. In other words, diagnosis of diabetic foot does not end with naming the current lesion, but continues with formal estimation of the probability of recurrence and limb loss.

Treatment of diabetic foot is effective only when all relevant pathogenic components are addressed simultaneously. No dressing can heal an ulcer that remains mechanically loaded, no antibiotic can compensate for unrecognized critical ischemia, and no vascular procedure is sufficient if a deep infection is not drained or if the patient resumes wearing traumatic footwear. Appropriate care is therefore multidisciplinary and must integrate offloading, debridement, infection control, correction of perfusion, metabolic treatment, selection of suitable dressings, patient education, and recurrence prevention.

For neuropathic plantar ulcers of the forefoot or midfoot, the cornerstone of treatment is plantar pressure offloading. Guidelines recommend a nonremovable knee-high device as first-line therapy, preferably a total contact cast or a walker rendered nonremovable, because this approach is most effective in reducing pressure and ensuring true adherence. If this is contraindicated or not tolerated, a removable knee-high device is used; ankle-high systems, appropriate therapeutic footwear combined with felted foam, or other less effective strategies are considered subsequently. The key concept is that offloading is not an accessory to wound dressing, but its biological prerequisite. In selected recurrent ulcers, particularly when a deformity creates a persistent pressure peak, corrective procedures may be required, such as flexor tenotomy for apical toe lesions, metatarsal head resection, Achilles tendon lengthening, or other prophylactic and curative surgical procedures.

Regular debridement of nonviable tissue and peripheral hyperkeratosis is another key component. Removing callus, fibrin, and necrosis allows proper visualization of the depth and extent of the lesion, reduces the bacterial burden, improves the granulation bed, and decreases pressure at the ulcer margins. Dressings should maintain an environment conducive to healing, manage exudate, and protect granulation tissue, but material selection must never obscure the fundamental principles. Recent guidelines also recommend selective use of advanced therapies: some options may be considered for ulcers that fail to heal despite optimal standard care, but many technologies proposed over time have not demonstrated sufficient benefit for routine practice.

When an ulcer does not improve adequately, the clinician must ask which link in the healing process remains unresolved. If ischemia is present, revascularization should be considered early. Absent pulses, markedly abnormal Doppler waveforms, low distal pressures, gangrene, infection associated with ischemia, or failure of the ulcer area to decrease substantially after several weeks of appropriate therapy require vascular surgical involvement. The choice among an endovascular approach, bypass, or a hybrid strategy depends on lesion anatomy, availability of the great saphenous vein, severity of limb threat, the patient's risk profile, and center expertise. The hemodynamic objective is to restore effective blood flow to the foot, ideally directed toward the ulcerated territory, within an integrated plan that also includes infection control, wound care, and offloading.

Infection management requires rigor. Clinically uninfected ulcers should not be treated with antibiotics because this does not accelerate healing and promotes resistance. When infection is present, treatment combines antibiotic therapy, surgical debridement of necrotic tissue, drainage of collections, and, when necessary, resection of infected bone. Initial empirical selection depends on clinical severity, depth, previous microbiological findings, recent antibiotic exposure, and the local epidemiological context; therapy must then be adjusted according to deep-tissue or bone cultures. Soft-tissue infections require variable durations, shorter for mild forms and longer for extensive or slowly resolving disease, whereas osteomyelitis requires an even more individualized approach based on the surgery performed and persistence of residual infected bone. Hospitalization and urgent intervention must not be delayed in cases with systemic compromise, sepsis, extensive necrosis, or suspected deep-compartment infection.

Active Charcot neuroarthropathy must be treated as a true functional emergency. The principle is immediate immobilization with a knee-high device, preferably nonremovable, combined with marked reduction of weight-bearing until clinical remission of inflammatory activity and osteoarticular stabilization. Continued unprotected walking during the early stages is one of the main determinants of foot collapse. Thereafter, the patient requires orthoses, custom footwear, and close surveillance to prevent ulcers over residual bony prominences. Recent recommendations do not support routine use of bisphosphonates or other antiresorptive pharmacological treatments as the cornerstone of therapy; management remains primarily mechanical, structural, and specialist-led.

Some adjunctive therapies may be considered in selected scenarios after failure of genuinely optimized standard care. In noninfected neuroischemic ulcers that do not show adequate progress, certain devices or specific dressings, such as sucrose octasulfate products, may have a role. In centers with appropriate expertise and resources, topical oxygen therapy or hyperbaric oxygen therapy may be considered as adjuncts for resistant ischemic or neuroischemic lesions. Negative-pressure wound therapy is mainly indicated for postsurgical diabetic foot wounds rather than uncomplicated nonsurgical ulcers. In every case, no advanced therapy replaces control of the main determinants of healing: offloading, perfusion, debridement, infection control, and organization of follow-up.

Secondary prevention begins while the lesion is still open. Every patient whose foot ulcer has healed should be considered in remission, not permanently cured, because recurrence risk remains very high. Custom therapeutic footwear, periodic risk monitoring, callus treatment, continuous education, daily foot inspection, attention to skin temperature in selected high-risk individuals, correction of pressure factors, and rapid access to the center for new red, warm, or fissured areas are therefore required. The true quality of diabetic foot care is measured not only by ulcer closure, but by the ability to prevent it from reopening.

Prognosis depends on lesion depth, the presence of ischemia, the extent of infection, possible bone involvement, the feasibility of proper offloading, the timeliness of revascularization when necessary, patient adherence, and the burden of systemic comorbidities. Superficial neuropathic ulcers that are promptly offloaded may heal with good outcomes; by contrast, neuroischemic, infected, recurrent ulcers or those associated with Charcot neuroarthropathy and kidney failure have a much poorer prognosis. Even when the local outcome is favorable, the overall prognostic significance remains substantial: patients with diabetic foot have a high risk of new ulcers, hospitalization, amputation, and death in the following months and years, particularly when chronic kidney disease and cardiovascular disease coexist. Diabetic foot should therefore be viewed as a clinical threshold marking entry into a phase of high systemic frailty.

The most frequent and immediate complication is ulcer recurrence. It occurs because skin closure does not automatically correct neuropathy, deformity, peripheral artery disease, abnormal load distribution, or skin fragility. If the patient resumes walking with high plantar pressures, unsuitable footwear, or untreated calluses, the most vulnerable site tends to reopen or a lesion develops at a new site exposed to compensatory biomechanical stress. This dynamic explains why remission, rather than permanent healing, is the correct concept and why follow-up must be lifelong.

The second major complication is deep infection, which may progress from cellulitis to abscess, tenosynovitis, fasciitis, septic arthritis, and osteomyelitis. Progression is promoted by neuropathy, which delays recognition, and ischemia, which reduces tissue response and effective antibiotic penetration. Osteomyelitis is particularly insidious because it may become chronic, maintain persistent drainage, prevent wound closure, and necessitate bone resection or partial amputation. In severe infections, systemic spread can lead to sepsis, metabolic decompensation, multiorgan failure, and markedly increased in-hospital mortality.

Another crucial complication is ischemic gangrene. When perfusion becomes critically inadequate, even minor trauma or apparently trivial lesions progress to dry or wet necrosis. Gangrene is not merely a local outcome of arterial disease, but the convergence of inadequate perfusion, superimposed infection, diagnostic delay, and inability to heal spontaneously. In the most severe cases, urgent amputation is required to control pain, infection, or systemic risk. It is important to remember that gangrene may develop in a patient with diabetes without the classic pain syndrome of critical ischemia because neuropathy attenuates symptoms.

Charcot neuroarthropathy also causes specific complications. Osseous and articular collapse profoundly alters foot geometry, creates pathological plantar prominences, and makes normal load distribution extremely difficult. The consequences include chronic friction- or pressure-related ulcers, mechanical instability, difficulty fitting footwear, reduced walking independence, and increased risk of amputation. When Charcot neuroarthropathy involves the ankle or hindfoot, loss of stability may compromise not only foot function but the patient's entire ability to stand and walk safely.

Amputations are the most visible complication, but they do not capture the full burden of the problem. A minor amputation may alter gait biomechanics and create new areas of overload, predisposing to further ulcers and an “amputation cascade.” A major amputation, in addition to anatomical loss, has an enormous impact on independence, rehabilitation, fall risk, depression, care dependence, and mortality. From a cardiovascular standpoint as well, an amputee belongs to an extremely high-risk population in which systemic events compete with the local wound outcome.

Finally, diabetic foot should be regarded as a complication with global prognostic consequences. Ulcers are often associated with chronic kidney disease, diffuse peripheral artery disease, coronary artery disease, heart failure, sarcopenia, and advanced frailty. The increased mortality observed after a new ulcer is therefore not due solely to infection or amputation, but to the fact that the lesion signals an organism that is already profoundly compromised. In a meaningful proportion of very old and multimorbid patients, assessment of complications must consequently also include realistic quality-of-life goals, proportionality of procedures, and shared care planning.