Abstract
Purpose
People with diabetes and Charcot arthropathy have higher mortality than people with diabetes without this complication. Are the causes of this higher mortality exclusively infectious or of a cardiovascular origin? We aimed to study aspects related to cardiovascular risk and inflammation in a population of people with type 2 diabetes with and without Charcot arthropathy.
Methods
A cross-sectional study was performed in people with diabetes and Charcot Eickenholtz III arthropathy, matched for sex and age, with two groups of people with diabetes without Charcot arthropathy with and without peripheral sensory-motor neuropathy, in the absence of active infection. All participants underwent clinical and laboratory evaluation at the time of the interview, and their cardiovascular risk was calculated according to the United Kingdom Prospective Diabetes Study (UKPDS) calculator.
Results
We evaluated 69 people with type 2 diabetes (21 with Charcot arthropathy, 24 with diabetic peripheral neuropathy and 24 without this neuropathy), with a mean age between 57 and 61 years and with a diabetes duration of more than 10 years. Patients with Charcot arthropathy had a longer duration of diabetes; more frequency of dyslipidemia; and higher levels of uric acid, microalbuminuria and C-reactive protein than the other two groups. A total of 73.9% of the people evaluated had high or very high cardiovascular risk according to the UKPDS score.
Conclusion
The people with type 2 diabetes presenting Charcot arthropathy had greater values of systemic inflammatory parameters, even in the chronic phase of the complication, with a higher risk of mortality unrelated to infections.
Keywords: Type 2 diabetes mellitus, Charcot arthropathy, Cardiovascular risk, Systemic inflammation
Introduction
Charcot arthropathy (CA) is a complication of peripheral neuropathy that affects the bones, joints, and soft tissues of the foot and ankle. Charcot arthropathy is characterized by early-stage inflammation that progresses with varying degrees of bone destruction, subluxation, displacement, and deformities [1]. Considered as a rare complication of diabetes, CA has a prevalence that varies between 0.1% and 0.9% [2]. This prevalence is probably underestimated due to a lack of diagnosis, since the initial presentation is very similar to an infection or dislocation, often leading to a delay in diagnosis [3]. This delay in diagnosis, in turn, leads to up to a fivefold increase in the number of complications during treatment [4].
The etiopathogenesis of this condition is not yet fully understood, but it is known that CA occurs in genetically predisposed individuals who present neuropathic alterations [3]. Regarding neuropathic alterations, peripheral sensory neuropathy leads to a loss of protective sensitivity allowing the gait to perpetuate the process of bone and joint destruction; motor neuropathy, which alters the structure of the foot leading to deformities such as a loss of the plantar arch; and autonomic neuropathy, which in turn promotes a neuromediated vascular reflex resulting in increased local peripheral blood flow with subsequent higher bone resorption [1]. Other causes, such as previous surgeries at the site, local inflammation, and bone metabolism dysregulation, may also contribute to the genesis of this complication [2].
With regard to cardiovascular mortality, diabetes mellitus (DM) is considered an independent cardiovascular risk factor, as individuals with DM have a two to four times increased probability of developing coronary artery disease (CAD) compared to people without diabetes [5]. The Diabetes Heart Study [6] showed that the factors with the greatest predictive power for the risk of acute coronary syndrome in people with diabetes were statin use and LDL cholesterol levels, followed by the glomerular filtration rate, microalbuminuria and C-reactive protein. In general, people with diabetes and Charcot arthropathy are more likely to die than people with diabetes without this complication. In this regard, the Sohn study evaluated a cohort of 1050 people with diabetes and found that the presence of Charcot arthropathy increased overall mortality by 23% [7].
Given the many gaps on the clinical aspects of people with diabetes and Charcot arthropathy, the main objective of our study was to evaluate aspects related to cardiovascular risk and systemic inflammation in a population of people with DM with and without CA. The specific aims were to find out which clinical and laboratory variables influenced the cardiovascular risk of people with diabetes, to assess the cardiovascular risk of these studied data. Our hypotheses are that among people with Charcot arthropathy, there would be a higher prevalence of cardiovascular risk factors such as arterial hypertension, smoking and dyslipidemia and markers of inflammation such as CRP. We also believed that people with CA would have a higher cardiovascular risk when using the UKPDS score and the Global Risk Score.
Methods
Study design and patients
A cross-sectional study was carried out at a diabetes referral service in Campinas University, São Paulo, Brazil. For the eligible population of the study, the following inclusion criteria were considered: adult and elderly patients of both sexes, diagnosed with type 2 diabetes, who were being followed up at the endocrinology outpatient clinic during the study collection period, between the years 2015 and 2017. For a sample of people with Charcot arthropathy, we selected people who were followed up at the diabetic foot outpatient unit and who were able to attend an extra day to the consultation to do a clinical interview. Initially, 24 people with CA were selected, who were matched by sex and age with another 24 people with peripheral sensory neuropathy and others without sensory neuropathy. At the end of the study, 3 people with CA were excluded from the study due to lack of neuropathy exam data.
We selected people with DM and CA, diagnosed by clinical (history of diabetes with sensory neuropathy, past inflammatory signs compared to contralateral extremity without history of trauma) and radiological (presence of fracture and joint dislocation in X-ray) findings. They were all in phase III according to the Eichenholtz classification stage, when there are absence of warmth, absence of swelling, absence of erythema, stable joint or fixed deformity [8], and identified as the Charcot group [9]. Other etiologies of this neuropathic complication were excluded. Subsequently, this group was matched by sex and age with two other groups of people with diabetes without CA divided according to the presence or absence of sensory-motor peripheral neuropathy at clinical diagnosis, called the PN and PNSA groups, respectively. The entire series was evaluated for clinical, demographic and laboratory characteristics. We chose to match the groups because we analyzed variables related not only to cardiovascular risk but also to the onset of neuropathy and its complications, such as Charcot arthropathy.
To avoid possible sources of bias, we excluded from the study people diagnosed with type 1 diabetes; people with infected plantar ulcers, malignancies, active inflammatory disease, New York Heart Association (NYHA) class III or IV heart failure, or severe liver disease (Child–Pugh class B or C); people seropositive for HIV or hepatitis C virus; people with psychiatric illnesses, vitamin B12 deficiency, alcoholism, hypothyroidism or any other clinical conditions that could interfere with the clinical evaluation of neuropathy.
One of the potential confounders in our sample is that, as Charcot arthropathy is a rare disease and people should be without inflammation or active infection in the limb, our group of people with CA was smaller when compared to the other groups in the study.
This study was carried out at the Diabetes and Diabetic Foot Services department of a tertiary hospital after approval by the local research ethics committee (CAAE 1,332,642).
Assessment of peripheral sensorimotor neuropathy
The assessment of peripheral sensorimotor neuropathy was performed by the Dick et al. [10] Sign and Symptom scores, validated and accepted by the American Diabetes Association [11]. The population studied was subjected to a questionnaire on peripheral neuropathy symptoms, the Neuropathic Symptom Score, which classifies the patient as having mild (3–4 points), moderate (5–6 points) or severe (7–9 points) symptoms, and the Neuropathic Impairment Score, which assesses pain, temperature, vibratory sensitivity, and Achilles reflex through physical examination, which classifies as having mild (3–4 points), moderate (5–6 points) or severe (7–9 points) signs [12]. People were considered to have peripheral neuropathy if they had moderate symptoms associated with mild Neuropathy Disability Score signs or if they had moderate signs with or without symptoms, excluding other causes of neuropathy such as vitamin B12 deficiency, alcoholism, hypothyroidism, or use of neurotoxic substances.
Clinical assessment
At the time of evaluation, demographic and clinical data were collected regarding age, sex, time since the diagnosis of diabetes, smoking, the presence of comorbidities such as systemic arterial hypertension and dyslipidemia, the presence of nephropathy, and previous psychiatric or cardiovascular disease.
Laboratory assessment
Laboratory assessment consisted of analyses of serum concentrations of fasting glucose, creatinine, HDL cholesterol, LDL, triglycerides, uric acid, glycated hemoglobin, vitamin B12, microalbuminuria and C-reactive protein.
Fasting blood glucose was assessed using a colorimetric enzyme glucose method, with reference values for people with diabetes ranging between 70 and 129 mg/dl according to the ADA [13]. For total cholesterol, its fractions and triglycerides, an enzymatic colorimetric method was used, and the reference values accepted for this population were as follows: HDL above 40 mg/dl for men and 50 mg/dl for women, LDL below 70 mg/dl and triglycerides below 150 mg/dl, and total cholesterol being the result of their sum [14]. For uric acid, a colorimetric enzymatic method was also used, with reference values between 3.5 and 7.2 mg/dl in men and 2.6 and 6 mg/dl in women. Glycated hemoglobin was analyzed by high-performance liquid chromatography (HPLC). Among people with diabetes, normal values may vary according to age, comorbidities and complications of the disease. Among people without diabetes, a value lower than 6.5% should be found. Immunoturbidimetry was used to analyze microalbuminuria, for which normal values are below 30 mg/24 h.
Creatinine was measured by a colorimetric kinetic method, with values between 0.4 and 1.4 mg/dl considered normal in adults. From the creatinine values, we calculated the glomerular filtration rate using the KDIGO [15] CKD-EPI equation. Vitamin B12 concentrations were measured using a chemiluminometric method, with concentrations greater than 300 pg/mL considered normal values, values from 190 to 300 pg/mL borderline, and values lower than 190 pg/mL deficient. C-reactive protein measurements as an indicator of cardiovascular risk were performed using an immunoturbidimetry method, with values above 0.3 mg/dl being considered indicators of cardiovascular risk.
Cardiovascular risk assessment
We used the Risk calculator UKPDS, recommended to estimate the chance that a person with diabetes will develop cardiovascular disease based on prospective cohort studies [16, 17]. The entire sample was diagnosed with type 2 diabetes, and the UKPDS calculator assessed age, sex, the duration of diabetes, smoking history, glycated hemoglobin, HDL and total cholesterol levels, systolic blood pressure and microalbuminuria.
The Global Risk Score, commonly used for populations with and without diabetes [14] was applied to the participants.
Statistical analysis
To describe the profile of the sample according to the variables under study, frequency tables were made for the categorical variables with absolute (n) and percentage (%) frequency values. For numerical variables, descriptive statistics were performed, with mean values, standard deviations, and minimum and maximum values. People with missing data were excluded from the study.
Pearson's chi-square test was used to compare categorical variables, and when necessary, Fisher's exact test was used. For numerical variables, the Kruskal–Wallis test was used, followed by Dunn's post-hoc test, the Mann–Whitney test and the ANOVA and Brown-Forsythe tests.
The significance level adopted for the study was 5%.
For statistical analysis, the computer program SAS System for Windows (Statistical Analysis System), version 9.4, was used (SAS Institute Inc, 2002–2008, Cary, NC, USA).
Results
We evaluated 69 people with type 2 DM, 21 of whom had Charcot arthropathy, 24 had diabetic peripheral neuropathy and 24 had no diabetic neuropathy. The mean age ranged between 57 and 61 years, with no difference in age among groups. The mean time since the diagnosis of diabetes ranged between 12 and 18 years. The mean blood glucose was 167 ± 66,5 mg/dl, and the mean glycated hemoglobin was 8,78 ± 1,91%, with no difference among groups. Participants were also matched by sex, with 38 men and 31 women (Table 1).
Table 1.
Demographic characteristics of patients with peripheral neuropathy and CA, and the cardiovascular risk of people with type 2 diabetes mellitus with Charcot arthropathy and people with and without peripheral neuropathy
| Variables | Charcot Arthropathy | Peripheral Neuropathy | Without Peripheral Neuropathy | P Value | |
|---|---|---|---|---|---|
| Age (mean ± SD) | 61.9 ± 7.58 | 60.58 ± 8.16 | 57.88 ± 6.6 | 0.2589 a | |
| Time of diagnosis of diabetes mellitus (mean ± SD) | 18.19 ± 6.77 | 15.67 ± 5.93 | 12.08 ± 10.03 | 0.0420 a | |
| HbA1c (mean ± SD) | 8.83 ± 2.25 | 9.08 ± 1.65 | 8.43 ± 1.84 | 0.5177 a | |
| Sex (n, %) | Male | 13 (61.9%) | 16 (66.67%) | 9 (37.5%) | 0.0956b |
| Female | 8 (38.1%) | 8 (33.33%) | 15 (62.5%) | ||
| High blood pressure (n, %) | 17 (81%) | 18 (75%) | 17 (70.8%) | 0.7334b | |
| Smoking (n, %) | 6 (28.57%) | 8 (33.33%) | 4 (16.67%) | 0.4014b | |
| Dyslipidemia (n,%) | 14 (66.67%) | 8 (33.33%) | 5 (20.8%) | 0.0055b | |
| Symptom score (mean ± SD) | 4.95 ± 3.17 | 4.54 ± 1.79 | 0.71 ± 1.37 | < 0.0001 a | |
| Sign score (mean ± SD) | 8.52 ± 1.69 | 6.79 ± 2.25 | 1.04 ± 1.71 | < 0.0001 a | |
| UKPDS risk | Intermediate | 3 (14.3%) | 4 (16.7%) | 11 (45.8%) | 0.625b |
| High | 9 (42.9%) | 13 (54.2%) | 9 (37.5%) | ||
| Very high | 9 (42.9%) | 7 (29.2%) | 4 (16.7%) | ||
SD (standard deviation); HbA1c (glycated hemoglobin); UKPDS Risk: assessment of cardiovascular risk according to a calculator. a: based on the Kruskal–Wallis test, followed by Dunn's test to determine differences. b: based on the chi-square test
Comparison among patients with Charcot arthropathy and patients with and without peripheral neuropathy
There was no difference among groups regarding the presence of a diagnosis of arterial hypertension or past or current smoking (Table 1).
People with Charcot arthropathy had a longer time of diagnosis of diabetes than those without peripheral neuropathy (p = 0.042) (Table 1).
Patients with Charcot arthropathy had dyslipidemia, identified by the use of statins, more frequently than patients with peripheral neuropathy and without peripheral neuropathy (p value 0.0055) (Table 1). There was no difference in cholesterol, HDL or triglyceride values among groups, and LDL values were above the target for patients with diabetes, with no difference among groups. In the laboratory assessment, the glomerular filtration rate was lower in patients with Charcot arthropathy and peripheral neuropathy than in those without neuropathy (p = 0.0054). Uric acid, microalbuminuria and CRP were higher in patients with Charcot arthropathy than in those with and without neuropathy (p = 0.0081, < 0.0001, and 0.0003, respectively) (Table 2).
Table 2.
Laboratory characteristics of people with type 2 diabetes mellitus with Charcot arthropathy and people with and without neuropathy
| Variables | Charcot Arthropathy | Peripheral Neuropathy | Without Peripheral Neuropathy | P Value |
|---|---|---|---|---|
| Fasting blood glucose (mg/dl) | 166.90 ± 66.57 | 154.38 ± 65.97 | 153.58 ± 69.01 | 0.6240a |
| GFR (ml/min/1,73m2) | 56.24 ± 28.05 | 69.33 ± 22.96 | 82.04 ± 18.05 | 0.0054a |
| Uric acid (mg/dl) | 5.71 ± 1.06 | 5.23 ± 1.8 | 4.49 ± 1.2 | 0.0081a |
| Total cholesterol (mg/dl) | 168.52 ± 38.11 | 167.88 ± 49.73 | 159.33 ± 43.34 | 0.5047 a |
| LDL cholesterol (mg/dl) | 90.43 ± 29.04 | 91.83 ± 36.53 | 94.71 ± 35.18 | 0.9130 a |
| HDL cholesterol (mg/dl) | 41.48 ± 10.35 | 41.33 ± 11.68 | 44.58 ± 10.12 | 0.4806 a |
| Triglycerides (mg/dl) | 185.86 ± 92.94 | 190.33 ± 142.71 | 135.75 ± 62.85 | 0.1651 a |
| Vitamin B12 (pg/mL) | 479.61 ± 182.24 | 365.17 ± 128.07 | 396 ± 143.5 | 0.0743 a |
| Microalbuminuria (mg/24 h) | 526.04 ± 845.73 | 146.07 ± 414.56 | 82.97 ± 138.78 | < 0.0001 a |
| C-reactive protein (mg/dl) | 7.11 ± 6.54 | 1.51 ± 2.14 | 3.48 ± 4.09 | 0.0003 a |
Data are represented as the mean ± standard deviation. GFR (CKD-EPI glomerular filtration rate);. a: based on the Kruskal–Wallis test, followed by Dunn's test to determine differences
People with Charcot arthropathy had the highest levels of mean uric acid when compared to those with and without peripheral neuropathy ( 5.71 ± 1.06 mg/dl; 5.23 ± 1.80 mg/dl; 4.49 ± 1.20 mg/dl, respectively, p = 0,0081) (Table 2).
Among the patients evaluated, 73.9% had high or very high cardiovascular risk according to the UKPDS calculator. When we evaluated patients according to the Global Risk Score for cardiovascular risk stratification, we found that due to the presence of diabetes, the mean age, the presence of comorbidities such as arterial hypertension or smoking history, and the exclusion of patients with past myocardial infarction or stroke, we found that only one patient was at intermediate risk and the others at high risk.
Discussion
We evaluated people with type 2 diabetes with more than 10 years of diagnosis and glycemic control outside the established therapeutic targets for their age group [18]. Dyslipidemia, higher levels of uric acid, microalbuminuria and C-reactive protein (CRP) and lower glomerular filtration rates were associated to patients with CA. Regarding cardiovascular risk, we found that the majority of our population, regardless of neuropathic complications, had a high or very high risk of cardiovascular disease.
A longer time since the diagnosis of DM was observed in people with Charcot arthropathy in relation to those without neuropathy, and the data are still conflicting in the literature. A study [19] that evaluated people with type 2 diabetes did not show “time since diabetes diagnosis” as a risk factor for the onset of Charcot arthropathy when compared to people with diabetic neuropathy. However, older age and the time since the diagnosis of diabetic foot (since the first ulceration) have been confirmed as risk factors for Charcot arthropathy. Similarly, another study that evaluated 124 consecutive people with type 2 diabetes (47 with Charcot arthropathy, 37 with peripheral neuropathy without CA and 40 with uncomplicated diabetes) [20] found no difference in the time since the diagnosis of diabetes among groups among those approximately 19 and 20 years old. Thus, the glycemic control (mean glycated hemoglobin of 8.5%) was worse than the verified in our study, a factor that, despite our population was outside the therapeutic targets at the time of data collection, does not allow further conclusions since the data does not let the construction of a longitudinal evaluation.
A case–control study [21] which evaluated people with type 2 diabetes and Charcot arthropathy and others without complications, observed a higher percentage of people with more than 10 years since the diagnosis of diabetes in the Charcot arthropathy group. Petrova et al. [22] found correlations between age and the duration of diabetes and the onset of Charcot arthropathy in people with type 1 diabetes but not in those with type 2 diabetes.
Charcot arthropathy is more commonly shown in people with diabetes for a longer period of time due to its pathophysiology, which is related to severe peripheral neuropathy and small, painless repetitive traumas [23]. As we know, the longer the time since the diagnosis of diabetes, the greater the prevalence of peripheral neuropathy, the possibility of exposure to trauma and the chances of CA occurrence [24].
Renal function decline represents a factor related to higher cardiovascular risk, and interestingly, the glomerular filtration rates in people who had Charcot arthropathy were lower than those in people without peripheral neuropathy, indicating greater impairment by diabetic nephropathy. The glomerular filtration rate of people without peripheral neuropathy did not reach levels compatible with hyperfiltration, 82 mL/min/1.73 m2, while people with Charcot presented 56 mL/min/1.73 m2. Corroborating the diagnosis of diabetic nephropathy, people with Charcot arthropathy presented higher urinary albumin excretion than those with and without peripheral neuropathy. This finding is similar to the literature, as a study [25] which evaluated the clinical characteristics and evolution of 164 people with CA, 150 of whom had type 2 diabetes, observed that these people were referred later to specialized centers and had a greater chance of renal impairment. Furthermore, microvascular or vasomotor dysfunction, one of the findings in diabetic nephropathy associated with autonomic neuropathy, could be the link between pathophysiology of Charcot arthropathy and nephropathy [26].
Another systemic inflammation parameter studied was uric acid. We found that people with CA had higher levels of this metabolite than the other groups of people with diabetes, even though they did not yet have hyperuricemia per se. Uric acid is a product of purine metabolism in humans and a marker of oxidative stress. This hyperuricemia-induced oxidative stress can cause insulin resistance, diabetes, and cardiovascular disease. A Chinese systematic review [27] verified that people with type 2 diabetes and peripheral neuropathy had higher values of uric acid, with or without hyperuricemia. Similar results were found in a study carried out in Canada [28], which also found a correlation between higher uric acid values (but still within the normal range) and the severity of peripheral sensory neuropathy manifestations among people with diabetes. A proposed reason for this result is that uric acid levels are higher in people with CA as a consequence of a greater predisposition to complications and perhaps with genetic factors that would allow exacerbated individual responses in relation to deleterious pathways with greater oxidative stress and its impacts [29].
The higher CRP levels among people with Charcot arthropathy than among those without the complication was also a relevant finding in our study and similar to the literature. Our results, although performed in people with CA in the chronic phase (EIII), were very similar to those of the Sinacore et al. [30] carried out with 18 people with peripheral neuropathy due to diabetes and Charcot arthropathy in the acute phase (Eichenholtz I and II) and 19 people with neuropathy but without CA. They evaluated both groups at baseline and after 1 year and perceived that those with CA had higher levels of inflammatory markers, such as CRP and ESR, at the time of the first assessment that, as in our series, remained elevated even after 1 year of follow-up. C-reactive protein, an already well-established marker of systemic inflammation and cardiovascular risk, was found to be higher among people with CA, probably due to the classic factors that increase it: longer disease duration, with subsequent longer exposure to hyperglycemia; high prevalence of dyslipidemia; and increased inflammatory activity in the affected extremities verified by increased osteoclastic activity and bone lysis [31].
In this study, we evaluated the Global Risk Score to stratify people's cardiovascular risk and found that due to the presence of diabetes, a mean age over 60 years, the presence of comorbidities such as arterial hypertension or smoking history and the exclusion of patients with previous myocardial infarction or stroke, only one person was classified as having intermediate cardiovascular risk, and the others were classified as high risk. In this group of people with type 2 diabetes, the UKPDS score allowed to differentiate the cardiovascular risk, which was not possible with the Global Risk score, as supported by some Societies of Cardiology [14]. The Global Risk Score, created to assess cardiovascular risk in the general population, may include some more nonspecific parameters in relation to the higher cardiovascular risk of people with diabetes, so it was not accurate in differentiating risk in this population. The UKPDS calculator, developed after an extensive study specifically with people with diabetes, in our study, better differentiated cases of greater or lesser severity.
The main limitations of the study was the small number of patients. However, Charcot arthropathy is considered a rare complication of diabetes, due to either the patient's low perception and lack of specialized help or the early amputation of the lower limbs suffered by these patients.
The strengths of our study are the fact that it was carried out in a referral service for the treatment of diabetes complications, only with people with type 2 diabetes, with comparisons between the population with Charcot arthropathy and those with and without peripheral neuropathy. We assessed clinical and laboratory parameters of glycemic control and related to systemic inflammation. Although Charcot arthropathy is still a clinical situation that demands much discussion and understanding of its pathophysiology, comparative studies such as ours open paths to new discoveries for its treatment and prevention.
Based on the data presented above, we concluded that, in our sample, people with Charcot arthropathy had greater systemic inflammation, even in the chronic phase of the complication, than people without this complication. This finding indicates that people with CA merit increased focus on the risk of mortality unrelated to infections or the amputation of extremities. Additionally, people with Charcot arthropathy had a higher prevalence of other complications of the disease, such as diabetic nephropathy, further increasing their cardiovascular risk.
Therefore, in addition to care for the lower limbs, we suggest that such people be treated as having a very high cardiovascular risk, with indications for strict control of arterial hypertension, DM, dyslipidemia and more attention to the precocious treatment, safe and protective measures against cardiovascular and renal changes.
Our database included 69 outpatients from a single tertiary center in Brazil who had been followed due to diabetes complications.
It was a cross-sectional study and could not represent the whole diabetic population. Despite this, we believe that these findings reinforce the need for early assessment, not only of all the specific aspects related to Charcot arthropathy, but also of the other clinical aspects related to DM and the myriad of laboratory alterations that make up its framework, in order to adopt measures that may help to reduce, or at least postpone amputations and deaths. Further studies should be conducted to explore the association between increased cardiovascular risk and Charcot arthropathy.
Funding
DEZ-W has a research grant from National Council for Scientific and Technological Development (CNPq) 303068/2021–3.
Declarations
Conflicts of interest
We declare that we had no personal, academic or financial conflicts of interest in the preparation of this article.
Footnotes
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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