Discussion
Diabetic foot ulcers are one of the most serious complications of diabetes mellitus that can result in amputation. Diabetic foot ulcers usually progress with infection, and early diagnosis and effective treatment is very important in preventing amputation.4For this reason, previous studies have emphasized biomarkers that show both the severity of infection and the amputation rate, and which can be used in early diagnosis.21 Among these biomarkers, CRP, WBC, procalcitonin and ESR levels related to infection were especially emphasized22, 23, and HbA1c levels were examined with regard to the amputation rate.24 These parameters can provide an evaluation of diabetic foot ulcers in terms of infection and diabetes, while IMA can allow these patients to be evaluated from a different angle. IMA is a molecule formed by the modification of albumin as a result of ischemic damage. The popularity of IMA has been increasing recently and its association with ischemic injury-related diseases has been demonstrated.
In this present study, we aimed to determine the predictive value of IMA in diabetic foot ulcer patients and compare them to CRP results, as well as reviewing the relationship of IMA levels with diabetic foot ulcers according to the Wagner classification. We found that the levels of IMA in the diabetic foot patient group was significantly higher than those of the healthy control group. In previous studies, IMA levels have been considered in patients with diabetes and in patients with diabetes complications. Piwowar et al. reported that IMA levels in patients with type 2 diabetes were higher than the healthy control group.13 In addition, IMA levels in diabetic nephropathy25 and diabetic retinopathy26 have been reported to be higher than the corresponding control group. Gunduz et al. reported that IMA levels of lower extremity ischemia patients and a healthy control group were compared and IMA levels of the patient group were significantly higher.27 Muhtaroğlu et al. examined IMA levels in diabetic foot patients and reported that they were higher than the healthy control group.28 The results from our study support the results of Muhtaroğlu et al. When we investigated the CRP result, the CRP level in the diabetic foot patient group was significantly higher than the healthy control groupSimilar results were reported in previous studies.21-23. These results show that IMA also plays an important role in the pathogenesis of diabetic foot patients.
In our study, we investigated the IMA levels in subgroups created according to the Wagner classification, and this is the first study that reports IMA levels in diabetic foot patients in terms of the Wagner classification. We found the highest IMA levels in Wagner grade 5. There was no significant difference between Wagner grade 1, 2 and 3 in terms of IMA levels. The level of IMA in Wagner grade 4 was significantly higher than those of Wagner grade 1, 2 and 3. We are unable to discuss these results in detail since IMA levels in diabetic foot patients, which were previously classified according to the Wagner classification, were not examined. The highest CRP levels were determined in grade 5 in subgroups created according to the Wagner classification, but there was no statistically significant difference between grades 4 and 5. Also, there was no statistically significant difference between grade 1 and 2 in terms of CRP. Grade 3 CRP levels were found to be significantly higher than grade 1 and 2, and significantly lower than grade 4 and 5. Raheem et al. divided diabetic foot patients into subgroups according to the Wagner classification and examined their CRP levels. They reported that there was no statistically significant difference between grade 1 and 2 and that the highest CRP levels were detected in grade 5.29 Hadavand et al. compared only the CRP levels of class III and IV and found that the CRP levels of class IV were statistically significantly higher than the class III.22 Jeandrot et al. created subgroups using a different method of diabetic foot classification and examined their CRP values. While determining the highest CRP value in grade 4 in their studies, they reported that there was no statistically significant difference between the grade 1 and healthy control groups.23 According to our results, both IMA levels and CRP levels are closely related to the Wagner classification, which evaluates according to the severity of infection, osteomyelitis, and necrosis. In our study, we classified the diabetic foot patients according to the presence of osteomyelitis and examined the IMA and CRP levels. We found that IMA and CRP levels were significantly higher in diabetic foot patients with osteomyelitis than in patients without osteomyelitis. These results support that IMA is related to the severity of infection in diabetic foot patients.
In our study, ROC analysis was performed to show the predictive value of IMA and CRP in subgroups created according to the Wagner classification. When the ROC curves are examined, it can be seen that the predictive value of CRP is higher than IMA in the distinction between grades other than grade 4-5. In distinguishing between Wagner grades 4 and 5, IMA AUC, sensitivity and specificity values ​​were higher than those of CRP. According to our knowledge, there is no study examining the predictive value of IMA in the Wagner classification: this assessment was made for the first time in our study. Studies investigating the predictive value of CRP in distinguishing the classification, severity and presence of osteomyelitis have been conducted. Hadavand et al. reported that CRP has high sensitivity and specificity, especially in determining the presence of osteomyelitis in diabetic foot patients.22 However, it should not be forgotten that CRP is an acute phase reactant and naturally increases in many infection-related diseases. In other words, CRP levels can also increase in a different complication, not associated with the diabetic foot. Jeandrot et al. examined the predictive value of CRP and procalcitonin in the separation of non-infected (grade 1) and infected (grade 2) patients, reporting that there was no significant difference between CRP and procalcitonin in terms of predictive value and that the combination of CRP and procalcitonin gave much better results.9 IMA was more specific and sensitive than CRP in the distinction of grade 4 and grade 5 in patients with diabetic foot ulcers . This may be due to the development of endothelium-induced ischemia in tissues. Therefore, in these patients, besides blood, glucose level regulation, control of HbA1c levels and detection of infectious agents, ischemic conditions may also be considered.
There are some limitations in our study. One of these limitations is that the duration of diabetes in patients is unknown, so we could not clarify whether the duration of diabetes has an effect on IMA levels. Another limitation is that the sample size of our control group is relatively low. In advanced studies, the effects of diabetes duration on IMA levels can be examined by creating larger sample sizes.
In conclusion, our data showed that IMA may play a role in the pathogenesis of diabetic foot ulcers. In addition, it has been determined that IMA levels have high sensitivity and specificity in distinguishing Wagner grade 4 and 5 diabetic foot ulcers, especially when the infection is severe. Therefore, it may be clinically useful to examine IMA levels in the classification, progression and management of diabetic foot ulcers.