Diabetic foot disease is caused by a range of pathologies including dystrophic lesions of the peripheral nerves, arterial occlusive lesions, and the tendency to combine bone and soft tissue infections. Foot ulcers are one of the most common and major complications of diabetes mellitus. According to the literature, about 5% to 10% of diabetic patients have foot ulcers of varying degrees, and foot ulcers mostly occur 10 years after the onset of diabetes; about 45% of those with disease duration of more than 20 years have neurological disorders of the foot; 1% of diabetic patients need amputation treatment, and their amputation rate is 15 times higher than that of non-diabetic patients. Diabetes mellitus is also listed as the 3rd most prevalent disease range in China in recent years. Severe foot ulcers cause a serious decline in the quality of life of patients, and bring certain difficulties in treatment, especially the long course of treatment, high medical costs, must be given great attention.
A. Classification and classification of diabetic foot lesions
Common diabetic foot lesions, mainly the occurrence of ulcers and gangrene. Ulcers can be of varying depths, with or without infection. Gangrene can be localized or can involve the entire foot. Rarely, the foot lesions are Charcot’s osteoarthropathy and neurodegenerative edema. The main causes of diabetic foot ulcers and gangrene are: neuropathy, vascular disease and infection. They are classified by etiology as: (1) neurological; (2) ischemic; and (3) mixed. There are two main classification methods according to the severity of the disease and the foot ulcers. The first is the Wagner grading method, which has 5 grades.
Grade 0: the presence of risk factors for the development of ulcers on the foot, but no current ulcers.
Grade 1: superficial skin ulcers with no clinical evidence of infection
grade 2: deep ulcers that may involve tendons or joint capsules, often combined with cellulitis, without abscesses or osteomyelitis
Grade 3: deep ulcers with bone histopathy, abscesses or osteomyelitis
Grade 4: ischemic ulceration with limited gangrene (toe, heel or forefoot dorsum). Necrotic tissue may be co-infected and combined with neuropathy.
Grade 5: Extensive total foot gangrene, requiring amputation.
The second is the Liverpool grading method, which is divided into primary and secondary.
Primary includes neurologic, ischemic, and neuro-ischemic factors.
Secondary includes both uncomplicated and complications (such as cellulitis, abscess or osteomyelitis).
II. Pathogenic factors and clinical manifestations
Some high-risk factors that can easily lead to foot ulcers and gangrene must be noted and given high priority.
① neuropathy: sensory nerves, motor nerves and autonomic nerves, etc.
(ii) Peripheral vascular lesions.
(iii) Previous history of foot ulcers.
④ foot deformities, such as eagle claw foot and Charcot foot.
⑤ foot callus.
(vi) Patients with blindness or severely diminished vision.
(vii) Combined renal pathology, especially chronic renal failure.
⑧ elderly people, especially those living independently.
(⑨) Those who are unable to observe their own feet or have dulled senses.
(⑩) Those who lack knowledge of diabetes.
Neurotrophic disorders and ischemia are the main causes of foot ulcers in diabetic patients, and both often coexist. The cause of neurotrophic disorders caused by diabetes is not well understood, and is generally thought to be related to factors of metabolism and blood supply. Chronic hyperglycemia can lead to degeneration of peripheral nerve dystrophy, which manifests in the foot as symmetrical distal polyneuropathy.
Hyperglycemia is the main feature of type 2 diabetes. type 1 is characterized by loss or hypoglycemia of insulin production by pancreatic islet cells. The former is characterized by impaired function of insulin secretion and antagonism to insulin in response to environmental and genetic factors. Hyperglycemia affects the development and progression of diabetic complications through two pathways. Glucose can be reduced to sorbitol and accumulate in certain tissues, such as nerves, retina and kidneys, through a variety of complex mechanisms. Another metabolic disorder may be protein glycation, including hemoglobin, albumin, collagen, fibrin and lipoproteins. Glycated proteins may be associated with damage to both small and large blood vessels in people with diabetes. During fasting hyperglycemia, the body is in a catabolic state, causing a negative nitrogen balance due to protein breakdown and glycogen isogenesis. There are several other factors that can aggravate the load on the patient’s foot. Glycogen glycation can lead to thickening of the dermis and loss of elastic fibers, resulting in thickened tissue and reduced suppleness, and keratin can also undergo glycation, making the entire skin layer stiff and thus limiting joint movement.
1.Neurotrophic disorders
Peripheral neuropathy occurs during the lesion process in diabetic patients, which is caused by the denervation of sensory and motor nerves due to defective Schwann cell metabolism. The clinical manifestation of this lesion process is a delay in the rate of nerve conduction. Light microscopic examination reveals a thickening of the basement membrane surrounding the Schwann cells, and the myelin sheath often ruptures during the progression of the lesion. Nerves in remote portions of the limb are frequently affected, with myelinated and unmyelinated nerve fibers equally involved. Some diabetic patients have decreased anterior horn cells and increased gliosis of the spinal cord bundles. The cause of these nerve disruptions may be a factor in the occlusion of trophoblastic vessels on the surface of the nerve bundles. This process shows damage to motor and sensory nerves. When peripheral neuropathy occurs, it begins as more extensive demyelination of the most remote sites than proximal sites, followed by neuropathy, but more slowly. It may manifest as nocturnal limb spasms and sensory abnormalities, loss of tactile and pain sensation, and finally, loss of deep tendon reflexes. This indicates a gradual loss of protective function of the nervous system.
(1) Motor neuropathy: The main manifestation is the weakness of the inner tarsal muscles of the foot, which causes an imbalance between the long flexor and extensor tendons, resulting in a typical arched foot with claw-shaped toes. The fat pad under the metatarsal head is displaced distally, weakening the support under the metatarsal head. Normally, the toe can support up to 30% of the body weight applied to the foot, increasing to 50% in some cases. In severe claw toe, the toes do not bear weight, thereby increasing the load on the metatarsal heads, and Gooding et al. reported that in diabetic neuropathy, the fat pad under the metatarsal heads and under the heel atrophies, increasing the pressure in both areas. In diabetic foot ulcers, 90% occur in the area of greatest pressure. In recent years, scholars have found that changes in the collagen and elastic fibers of the skin layer of the foot in diabetic patients, such as tissue thickening and stiffness, can further cause restrictions in joint movement. In this case, the pressure on the affected foot can easily lead to the occurrence of ulcers.
(2) Sensory neuropathy: Depending on the main affected sensory nerve fibers, there are two different manifestations: painful or painless. Painless neuropathy is the most important cause of ulcers. Sensory neurotropic disorders reduce protective functions such as touch and pain, resulting in ulcers due to frequent trauma to the affected foot.
(3) Sympathetic neuropathy: In addition to some systemic symptoms, such as upright hypotension and diarrhea, the foot shows loss of sweat gland function, causing dry and cracked skin. In addition, the regulation of microcirculation in the foot is diminished due to changes in vasodilation and contraction functions, resulting in increased blood circulation and the opening of short circuits between arteries and veins. This is also the cause of ulcers due to reduced blood supply to the skin layer.
The tissue structure of the normal human foot is tough and can withstand a pressure of 100 kg/cm2 without breaking when there is no lesion in the sensory nerves. In severe cases of diabetic neuropathy, the affected foot does not feel anything even when it is traumatized by a sharp object. Neurotrophic ulcers are mainly caused by loss of protective sensation and pressure, but the patient has a normal blood supply and most often occur on the plantar aspect of the foot, corresponding to the 1st, 2nd and 5th metatarsal heads. It is characterized by deep ulcers surrounded by thickened keratinized tissue, with a reddish base, easy bleeding, no pain, warm feet and palpable arterial pulsations. Brooks reported that sympathetic neuropathy of the affected foot, which increases blood flow and leads to osteoporosis and injury of the foot, is associated with the occurrence of Charcot deformity.
2, ischemic disease
About 50% of diabetic patients develop lower extremity atherosclerotic occlusive lesions 10 years after the onset of the disease, the prevalence of which is four times higher than that of non-diabetic patients. 1998, Laing reported that the incidence of lower extremity atherosclerosis in type 2 diabetic patients was 20 times higher than that in the control group. Those who develop atherosclerosis due to diabetes at a younger age have a more rapid progression and a poorer prognosis. In addition to diabetes, hypertension, smoking, hyperlipidemia, and obesity are also factors that contribute to the development of atherosclerosis in diabetic patients. The pathological changes of atherosclerosis in diabetic patients are not significantly different from those in non-diabetic patients, but the former are characterized by sclerotic lesions that rarely occur in the main-iliac artery but are mostly confined to the beginning segments of the tibial and peroneal arteries, with the distal arteries still open and can be reconstructed. Sometimes the distal superficial femoral arteries are also involved, showing extensive luminal narrowing or occlusion of these arteries, while the dorsalis pedis artery and the arteries of the foot are mostly uninvolved, and there are no occlusive lesions in the microcirculation of the foot. The arteries of the lower extremities and feet of diabetic patients often have intimal calcification, and the middle layers of the arteries of older patients or those with a longer duration of disease may also become calcified, but the arterial lumen remains open. According to statistics, the rate of arterial calcification is 94% in patients with disease duration of more than 35 years, with coexisting neurological and vascular lesions, or with Charcot joint deformity, atherosclerosis can develop within a short period of time after the onset of the disease. Although calcification is present in the middle layer, the middle layer and lumen of the vessel are still relatively normal, so tying a tourniquet locally often fails to occlude these calcified arteries. As a result, the ankle/brachial index of the affected limb often appears to be artifactually higher than normal, and sometimes this index can be as high as 2 or more. Many authors have suggested that diabetes invades the small arteries, decreasing blood flow in the microcirculation and manifesting as intimal thickening mainly of the basement membrane, including the vessels in the arch and metatarsal regions of the foot. Electron microscopic examination confirmed this pathological change of basement membrane thickening. Reiber et al. noted that in diabetic patients, the compensatory function for the formation of collateral circulation between the distal segment of the deep femoral artery and the peripheral arteries of the knee is diminished, and therefore, clinical manifestations of ischemia may occur at the beginning of the lesion.
After a certain period of low pressure in the ischemic foot, ulceration can occur. Once the ulcer has occurred, the local blood supply must increase several times before it can heal. Ischemic ulcers alone are rare, accounting for only 10% to 15% of diabetic foot ulcers, and about 1/3 of foot ulcers have both neurological and ischemic lesions. Ischemic ulcers tend to occur in the toes and heel, but not in the metatarsal head area. Ischemic feet can be affected by trauma (e.g., prolonged bed rest, burns, barefoot walking, tight shoes, etc.) leading to ulcer formation. Ischemic ulcers are characterized by cold skin of the affected foot, degenerative changes, no arterial pulsation that can be retrieved, no keratinized hard nodules around the ulcer, fibrous tissue at the bottom, not easy to bleed, and often painful when touched.
III. Clinical examination and complication management
1. Non-invasive vascular examination
Foot ulcers and surgical wounds must be evaluated for healing tendency, and no-loss techniques can be applied to determine arterial blood flow to the limb. Due to the increased calcification of small arteries and the middle layer of the vessel wall, it is difficult to compress the vessels during segmental arterial manometry testing of the limb. It produces abnormally high manometric readings in insulin-dependent individuals with long-term diabetes. The PPG (photoplethysmography) method of testing provides accurate and reproducible toe artery pressures based on the fact that the toe vessels are less likely to be diseased than the proximal ankle, metatarsal, and tibial vessels, so the toe artery can be indexed relatively accurately. Holstein and Lassen reported successful healing of local amputation wounds with toe artery pressures of 2.67 kPa or less, with only 9% of amputation wounds healing. Barnes reported successful wound healing even with toe artery pressures >3.33 kPa.
All other factors being equal, healing arterial blood pressure in diabetic foot wounds needs to be higher than the values found in non-diabetic patients. This is a combination of occlusive vascular disease and the result of high resistance and low flow. Toe artery pressure measurement is quite useful in evaluating patients with N and tibial artery lesions and patients with small vessel occlusions in the foot. The normal toe/brachial index is 0.75, and if the index is <0.25, it represents a severe occlusive lesion of the foot. By calculating the toe artery pressure index and determining segmental arterial pressure, the surgeon is able to evaluate different segments of the vascular tree lesion, from the femoral artery to the remote toe artery, and in each plane to quantify the relationship of arterial obstruction. Based on the value of the toe artery pressure, we can predict what treatment the patient needs.
2.Imaging
Imaging of the skeletal system should be performed in diabetic foot infections, as reflected by the ability to see the destruction of bone tissue, except for the degree of formation and progression of osteomyelitis lesions, where cortical irregularities indicate the early stages of the lesion. x-rays can also identify gas in the soft tissues, and the presence of gas in the soft tissues in diabetic foot infections is often not due to Clostridium perfringens, but may be a gas-producing anaerobic bacterial infection. Osteomyelitis is often reflected on radiographs due to inflammatory congestion and secondary deossification (deossification), including the finding of localized bone window holes, perforation of cortical or medullary bone, a process that is not easily detected until a certain amount of bone tissue has been resorbed. This usually occurs 2 to 3 weeks from the start of the infection.
Technetium (technetium) phosphorus bone scintigraphy is able to detect early lesions within a few days of the onset of infection. Gallium (gallium) scans are confined to infected bone tissue and are reflective of signs due to the combined action of granulocytes and bacteria. Indium (indium) labeled leukocyte studies are specific for infection because radiolabeled leukocytes are unable to bind into the infected area to interact with bone tissue metabolism, and when the infection is resolved, the scan is normal.
Magnetic resonance (MRI) examinations, with high tissue contrast, are very sensitive to soft tissue infections and are able to detect early changes when scanned with low signal intensity in T1-weighted and high signal intensity in T2-weighted scans. In additional bone structure studies, MRI is able to accurately visualize soft tissue and local infection information. Magnetic resonance angiography (MRA) examinations reflect stenosis and occlusion of the main arteries.
Color ultrasound and arteriography (DSA) examinations can provide more accurate and detailed information and data for diagnosis and clinical treatment, and provide a very useful objective basis for vascular reconstruction of blood flow channels.
3.Complications and their treatment
(1) Infection: After the formation of foot ulcer, it should be determined whether there is any complication of infection. A variety of bacterial infections can be present in any open ulcer of the foot. The most common ones are, in order, Staphylococcus aureus, Streptococcus, Gram-negative bacilli and certain anaerobic bacteria. However, the presence of bacteria in trauma cultures does not necessarily mean that the infection is concurrent, and a bacterial count of 105 per gram of tissue is generally considered to be the criterion for confirming the diagnosis of infection. Diabetic foot infections have a wide range of clinical symptoms, with the mildest finding being cellulitis, an inflammatory manifestation of the skin. It manifests as redness and warmth of the skin without defects in the skin structure. Infection invading the skin layers manifests itself as fluid-filled blisters of the skin, which are the result of increased capillary exudation, fluid leakage from the junctions of cells and cell rupture. This provides some protection to the injured tissue and the fluid may be a superior medium, however, if infected, pathogens can spread and cause surface damage at the site of injury and penetrate into the deeper tissues of the foot with some virulence.
Diabetic foot infections can exist in a hidden form. In deeper tissues it can manifest as subclinical symptoms of osteomyelitis and form superficial tissue infections via sinus tracts, and the resulting inflammatory fluid, which can flow down the fascia to the surface of the tissue, becomes chronically infected. Often the sinus tracts undergo epithelialization (epithelialization), which can lead to chronic damage at the site of infection. It is not uncommon for bone to be destroyed during this process, and patients are often overlooked for possible skeletal lesions due to the presence of neuropathy. When poor drainage of the sinus tract occurs, acute infection can obstruct the sinus opening and quickly produce an intraluminal abscess. In chronic osteomyelitis with acute soft tissue infection, the course of the disease may not be consistent with the patient’s chief complaint. Certain infections, such as epidermal infections or simultaneous infections of subcutaneous tissues, can interrupt the nutritional blood supply and cause progressive expansion of the disease, which in severe cases can lead to necrosis of the skin, fascia, and muscles of the affected foot, often manifesting as dry gangrene.
In case of concurrent cellulitis, there is redness and swelling around the ulcer, and the presence of deep abscess and osteomyelitis should be considered at this time. This is characterized by the onset of pain in the previously painless affected foot; the presence of gas in the soft tissues caused by gas-producing bacteria is seen on radiographs. In cases of diabetes complicated by osteomyelitis, there are some specific changes, including periosteal reaction, osteoporosis, bone cortical defects near the joint, and osteolysis. The periosteal reaction occurs in the metatarsal trunk, and osteolysis is mostly seen in the distal metatarsal and proximal phalangeal base. Crerand et al. reported that 99mTc bone scan and 111In-labeled leukocyte scan had a 90% confirmation rate for osteomyelitis. The sensitivity, specificity, and correctness of magnetic resonance examination are 88%, 100%, and 95%, respectively. Once osteomyelitis is detected, a thorough debridement must be done. The purpose of debridement is to.
① remove local bacteria.
② to promote healing.
③ To determine the absence of hyperkeratotic tissue and tumors present in the wound.
④To reduce local infection.
The wound must be examined daily to note the condition of the granulation, the presence of infection and residual scar tissue. A healthy trauma should have a moist environment for fresh granulation growth and no obvious bacterial infection present. This is because under these conditions, epithelial tissue growth, neoangiogenesis, and connective tissue synthesis are facilitated.
Several drugs are available for topical application after debridement. For example, silver ions can kill antibiotic-resistant strains of bacteria in wounds. Cardimom iodine releases a continuous local antimicrobial agent to remove bacteria and exudate.
Biological therapy (cytarabine) may be considered for wounds that have been treated conventionally and do not improve within 2 weeks. Currently, two FDA-approved products are Dermagraft and Apligraf, which are fibroblasts placed on a mesh made of absorbable material. Some recombinant growth factors that promote wound healing, such as platelet-derived generating factor (PDGF), i.e., FDA-approved Becaplermin, have also achieved good clinical efficacy.
(2) Necrosis: Gangrene of the toe is not uncommon. It can occur in patients with normal blood supply but neuropathy, or it can be caused by obstruction of the toe vessels by inflammatory cells and septic emboli. Gangrene of the toe is usually a dry gangrene. It extends proximally along tissue levels, such as the tendon sheath, and sometimes leads to necrotizing fasciitis. It is characterized by localized redness, swelling, fever, pain, and dark purple spots on the skin, and has a high mortality rate. Severe cases require amputation or toe amputation.
(3) Atherosclerotic occlusion: Since the arteries and microcirculation of the foot remain open, most scholars advocate timely arterial diversion of the distal segment of the affected limb. The indications for arterial reconstruction are resting pain, tissue ulceration or gangrene, ineffective conservative treatment, interstitial claudication, etc., which seriously affects life and workers and requires surgery after blood glucose control. Patients generally have good surgical tolerance, and surgical complications and mortality rates do not differ from those of non-diabetic patients. Reiber et al. reported that the patency and limb salvage rates were 87% and 92% at 3 years after reconstruction, and the limb salvage rate remained at 87% at 5 years, with a satisfactory surgical outcome of 1.8% mortality. For short segment stenosis and occlusion of the main trunk of the proximal artery of the lower extremity, the procedure of endoluminal shaping can be used in combination with surgical toe amputation or hemipleg amputation to repair the trauma and avoid major amputation above the ankle joint to maximize the protection of the limb and preserve the patient’s walking function (see figure). In the case of long segment lesions, the same diversion procedure is done as in non-diabetic patients. Both endoprosthesis placement and gene therapy have been applied clinically, and their effects are yet to be observed in the long term.