Diabetic foot syndrome

Diabetes mellitus has spread fr om 2.5 to 3.8% of the population with a doubling of the number of patients every 10-15 years. Among those older than 70 years have diabetes occurs in 10% of cases [1]. In Russia – about 10 million people with diabetes [2]. Diabetes mellitus type 2 is found in 10-20 times more common than diabetes insulin-dependent.
In diabetes increases sharply production of modified glycated low-density lipoproteins (LDL). Formation of immune complexes with glycated LDL increases their atherogenicity and contributes to the progression of atherosclerosis [3].

In diabetes type 2 also revealed pronounced metabolic changes in these patients are prone to obesity [4]. It should be borne in mind that the characteristic of diabetes type 2 so-called metabolic syndrome or insulin resistance syndrome naturally accompanied not only impaired glucose tolerance, but also dyslipidemia, arterial hypertension, visceral obesity, and prothrombotic status [5, 6].

Those with the "central" type of obesity, high levels of total cholesterol, triglycerides and very low density lipoproteins, high blood pressure and risk of vascular lesions arises even when "under-diabetic" (less than 6.1 mmol / l ) glucose level [7].

Microcirculatory disorders in diabetes compounded higher blood viscosity due to an increase in the content of fibrinogen, fibronectin, von Willebrand factor, C-reactive protein [8].

Currently, the prevalence of metabolic syndrome takes on the character of the epidemic, especially when it starts in childhood, which further leads to the earlier development of atherosclerosis [9]. Studies have shown a direct relationship with the increase in the degree of insulin resistance in peripheral vascular resistance, blood pressure and reduce blood flow through the peripheral vessels [10].

Prolonged hyperglycemia leads to glycation of proteins. Glycation of collagen can provoke atherogenesis receipt of lipoproteins into the extracellular matrix, making it more susceptible to oxidative modification. Studies in recent years show that diabetes develops "oxidative stress." Due to the reduction of antioxidant status increased production of free radicals, enzymatic disorder that largely determines the secondary organ complications of diabetes [11]. Even with a normal level of low density lipoprotein (LDL) may be detectable markers of oxidation, such as antibodies to oxidized LDL and LDL-containing immune complexes, which seems a predisposing factor for the development of vascular lesions [12]. However, attempts to improve the condition of vessels using long-term administration of antioxidants (vitamin E) did not lead to the desired result [13].

In addition, there is a relationship of diabetes with increasing tendency to thrombosis in the field of atheromatous lesions. In diabetes, increased adhesiveness and platelet aggregation, as well as different levels of coagulation factors and inhibitors of tissue plasminogen anticoagulant that helps potentially procoagulant state [14].

Diabetic microangiopathy is characterized by impaired capillary basement membrane structure, deposition of LDL in the vascular wall and proliferation of smooth muscle cells there. Related neuropathy contributes to narrowing of arterioles and precapillaries with increasing blood flow through the artery - venous shunts, which further depletes nutrition and gas exchange of peripheral tissues. This is accompanied by increased blood circulation in the skin increased with the surface temperature. Therefore, along with a reduction in sensitivity due to neuropathy may be feeling the heat and burning of the skin and feet, night pain [15].

Spotted quite a clear relationship of diabetes and atherosclerosis. When this occurs the formation of autoantibodies anti-tissues (anti-vascular and "sclerotic") and circulating immune complexes, complement and its C3 fraction accumulation. If diabetes is accompanied by hypertension and then proceed as described immunological disorders and more intensively promote atherosclerotic lesions as coronary and peripheral vessels. At the same time, these immunological changes precede of vascular clinical manifestations [16].

Vascular endothelium in diabetes has a smaller capacity for the synthesis of vasodilators and produces more vasoconstrictors and procoagulants. These features exacerbate vascular disorders in diabetes. In particular, the vascular endothelium in diabetes, both the 1st and 2nd type, has a lesser ability to synthesis NO, that promotes local vasoconstriction [12].
Circulatory disorders due to narrowing of the vascular lumen compounded increase the propensity to thrombosis. Leading role in this is observed in diabetes platelet activation with the release of microparticles and procoagulants [17, 18].

Adipose tissue is an important source of endogenous TNF-a and the expression of this cytokine increases in obesity [19]. Elevated levels of ketone bodies promotes greater intensity of lipid peroxidation and hydroxyl radicals in the vascular endothelium and in erythrocytes in diabetes type 1, which contributes to the development of vascular complications [20].

Attempts to usedrugsagainsthypercholesterolemia,can leadto a number ofadversecomplications also.So, clofibrate effectivelyreduced content ofatherogenic lipids, but in patients with diabetesincreasedmortality fromnon-cardiacdiseases.In particular, a 68% increasedmortalityof tumor diseases[21]. Moreover, the treatment with statins in patients with type 2 diabetes more significantly decreased the content of antiatherogenic HDL and increased triglycerides than for patients without diabetes [22]. In addition, the lipid-lowering effect of statins treatment leads to complications such as increased activity of liver transaminases in several times and with increased rhabdomyolysis with increased levels of creatinine phosphokinase (CPK) and signs of increasing muscle aches and weakness [23, 24, 25].

Occlusive vascular diseases with disorders of both central and peripheral circulation are almost constant and severe enough satellites diabetes. According to the U.S. National Commission on diabetes in these patients five times more affected limb gangrene ("diabetic foot syndrome") [26]. Bother subjective complaint body aches and muscle pain. In the pathogenesis of these disorders plays a decisive role in the deposition of sorbitol into peripheral nerves with the activation of the so-called “graft polyol” that reduces intraneural blood flow and leads to chronic hypoxia with functional and structural changes in the nerve trunks.

Conditions arise also for segmental demyelination of nerve fibers with slow speed of neural excitation. Upcoming polyneuropathy accompanied by disturbances as motor and sensory nerve fibers, as well as elements of the autonomic system. Proximal diabetic neuropathy is accompanied by severe pain due to inflammatory lesions of the nerves in patients with insulin dependent diabetes mellitus type 2 at age 50. Severe pain is not always amenable to steroid and cytostatic therapy [27].

Motor neuropathy is a cause of muscle weakness, atrophy and paresis. Sensory neuropathy leads to weaken of the protective sensitivity to pain, compression and of thermal damage. Therefore minor injuries go unnoticed. The patient does not respond to prolonged compression, even footwear, that breaks the supply of separate parts of the lower limb. Autonomic dysfunction accompanied by a condition similar sympathectomy with functional disorders of microcirculation. All this greatly increases the risk of trophic ulcers and gangrene of the foot [15, 28, 29].

The arising ulcers usually do not tend to heal, progressed and inevitably lead to amputation of the foot, not only, but also the tibia and femur even. Thus more than half of these patients over the next five years there is a need the contralateral limb amputation also. In the United States, wh ere diabetes affects about 16 million people, the annual made of 50-60 thousand amputations [30]. Foot ulcers are the most common problem in patients with type 2 diabetes. Diabetic foot syndrome is found in 15% of the 200 million people with diabetes worldwide [31].

Joining infection and gangrene thus often lead to amputation [18, 32, 33, 34]. Septic complications thus also are a common cause of death after surgery [35]. In the presence of lower extremity diabetic ulcers risk of mortality within 5 years ranges from 43% to 55%, and reaches 74 % of patients who have undergone an amputation. Cardiovascular diseases in this case are the main causes of death [36]. Moreover, in the next 10 months the mortality in patients undergoing high amputation, significantly higher than after sparing amputation [37].

In Western countries, more than 60% of non-traumatic amputations above or below the knee performed in diabetic patients [31]. In Eastern countries amputation below the knee held at 72% and above the knee – in 27% of diabetic patients [38]. In a cohort study conducted in the city of Turku (Finland ) for the period 1998-2002, the rate of amputations, both above- and below the knee, with occlusive diseases of lower limb arteries was 24.1 per 100 000 population for 1 year. In the same study, covering France, the need for lower limb amputations occurred at 15,353 people, among whom 7,955 were diabetes. In the latter case, the frequency of amputations was 378 per 100 000 population. Thus the need of amputation was 12 times higher in diabetic patients than in the other cases [39]. Moreover, 40% of amputations were performed for patients who had not previously been noted signs of arterial circulation disorders of the lower limbs, and turned out to be the main cause of diabetes and neuropathy [40].

In 34% of patients required consecutive amputation. Mortality in this group (210 patients) for the year was 52%, and total mortality during this period was 80% [41]. Need to re-amputation occurred between 23% and 60.7% of patients in the next 3 years. Moreover, the contralateral limb re-amputation conducted more frequently than the ipsilateral [42]. Of 3565 patients during the year required re-amputation in 26% and 30% of them died. Total costs for the treatment of such patients in the United States totaled $ 4.3 billion [43].

Overall, in the United States in 2007 was 17.5 million registered diabetic patients, and the overall cost of their treatment amounted to $174 billion [44]. Necrotic processes in the lower extremities in patients with diabetes may be limited to subcutaneous tissue, the development of fasciitis and even necrosis of muscle mass. In such cases, the need for high amputation occurs in 7.3%, 20.9% and 53.2%, respectively [45, 46]. High amputation proved necessary and after sparing amputation in cases of soft tissue inflammation activation or osteomyelitis [34].

In diabetic patients who took high amputation, detected signs also of arteriosclerosis obliterans of lower limb vessels [47]. Of the 210 patients with gangrene of foot amputations were performed in 110 (52%), of whom 45 required amputation above or below the knee.
Revascularization (angioplasty or peripheral vascular grafts) allow to postpone amputation in diabetic foot, but in those cases when they are not possible or ineffective, the indications for amputation occur much more frequently [48]. In such cases, the high amputation proved necessary in 13.4% of patients, and after 8.2% of cases they were held after peripheral angioplasty, 21.1% – after vascular bypass surgery and 59.2% – in the group of patients whom revascularization was not performed. At the same time, restenosis occurred in 16.7% of patients, shunt thrombosis – at 6.4% and recurrence of ulcers – in 12.6% of patients. Contralateral limb critical ischemia occurred in 39.9% of patients and 6.7% of them required high amputation. During four years of observations, 49.82% of these patients died, mostly due to coronary heart disease [49]. It should be noted that more effective revascularization was in non-diabetic vascular occlusive disease of the lower extremities [50].

The most commonly used methods of sanitation ulcer surfaces, orthopedic methods of unloading the damaged areas of the foot, sessions hyperbaro-therapy, thermography examination and others [32, 51]. 
         Thus, the presence of both immune and metabolic changes in this form of diabetes make reasonable use of efferent therapy at all stages of the disease. It is practically the only way to correct these complications – elimination of secondary metabolic disorders. Only by plasmapheresis can remove many damaging factors such as the circulating immune complexes, glycoproteins, lipids, uric acid, endothelins, antibodies to insulin and others [52]. Plasmapheresis in diabetes reduces thirst, polyuria, pruritus, the level of glycemia and glycosuria, improves blood rheology and microcirculation, and, most importantly, improves the sensitivity of cellular insulin receptors [5, 53].

Indeed,numerous studiesindicatethe favorable results ofthis treatment, its corrective influenceoncarbohydrate andlipid metabolism,coagulationfactorsin patients with diabetes, especially in combination withcoronary artery disease [54]. Withplasmapheresis removed inducers of blood cells aggregation(fibronectin, von Willebrand factor, fibrinogen, thrombospondin) [55]. Thisimprovesthesensitivitytodrugs, includinghypoglycemic[56].
A.O.Gavrilovet al.[57] reported the recoveryof microcirculatory disordersafter courses ofplasmapheresiswith increasingpain-free walkingdistance, healingof trophic  ulcersoramputationssuspendedwith gangreneof the toes. Thisconfirmsalso our ownexperience of usingmembrane plasmapheresisin diabeticangiopathy[58]. There is evidenceof a positive effectof plasmapheresisandtrophic ulcersshinsthat developedonthe basis of varicoseveins ornecrotizingvasculitis[59].
Treatment ofnon-healingtrophic ulcers of diabetic foot proved effectiveusingcascade plasmapheresis(reo-apheresis) also [56, 60, 61, 62]. Reo-adsorptionby passingplasmathrough a specialaffinity columnsSepharoseallowedsignificantlyreduce the concentration offibrinogen, fibrinand otherdegradation products, which significantly improves themicrocirculationin diabetic foot[63, 64, 65]. Unlikedrug therapy(alprostadil, pentoxifylline), plasmapheresis enhancessignificant reduction of erythrocytes andplateletsaggregation by removingtheir aggregationinducers(fibronectin, von Willebrand factor, fibrinogen, thrombospondin) [59]. 

Thus, thesedata indicate theimportance of the problem of diabetic foot syndrome and prospects of usingmethods of efferenttherapymainlyplasmapheresisin the treatment ofthis severevascular disease indiabetics.

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