The results of this study showed that there were specific ultrasound signs of LHT, and that ultrasonography could detect more LHT than can clinical palpation and could accurately measure the size and area of LHT. The years of insulin injection, whether to rotate the injection site, the frequency of needle use, and the number of daily insulin injections were the main factors affecting the development of LHT. LHT may influence the control of patients' blood glucose, leading to increased fluctuations in blood glucose.
No other studies to date have proposed specific criteria for detecting LHT with head-to-head comparison and validation of clinical palpation and ultrasound. This greatly limits the use of ultrasonography in LHT. Histopathological examination showed that LHT was formed by adipocytes, which abnormally enlarged to two to three times the size of normal adipocytes, and fibroblasts, and could invade the adjacent reticular fibrous membrane and surrounding connective tissue, though often without neovascularization [14].In this study, the following LHT ultrasound characteristics were innovatively summarized by combining previous studies in the literature [12, 13]: 1) the hyperplastic area is characterized by echogenic nodules (hyperechoic or isoechoic) with differences in echotexture from the surrounding normal tissue and interstitial edema (hypoechoic) around the hyperplastic nodules; 2) there is continuous thick fascial tissue or interrupted and distorted thin connective tissue around the hyperplastic nodules, though this may not be present in markedly obese individuals; 3) there is little or no neovascularized echogenicity within the hyperplastic nodules; and 4) the edges of the area are clear and there is no envelopment. The ultrasound features summarized in this study will provide a reference for the ultrasound diagnostic criteria of LHT.
In clinical practice, LHT is most commonly assessed by palpation. However, this method is less reliable and is associated with a high level of interclinical variability. Nurses with rigorous training in palpation techniques were able to show a 97% case detection rate, while general nurses demonstrated 34% of missed diagnoses [15]. The high rate of missed clinical palpation examinations for LHT was also suggested in the results of this study, which showed a 32.6% underdiagnosis rate of LHT assessed by physical examination alone compared to that of ultrasonography. Notably, in this study, a total of 144 LHT were detected by ultrasound and only 67 by physical examination, resulting in a 53.5% underdiagnosis rate by physical examination alone compared to ultrasound for LHT. In addition, this study found that when the area of LHT was less than 30 mm2, the leakage rate of physical examination was as high as 95.9%. In addition, as the area of hyperplasia decreased, the leakage rate of physical examination increased. Therefore, when LHT lesions are small, physical examination alone often results in a greater degree of underdiagnosis. To the best of our knowledge, this study is the first to explore the leakage rate of ultrasound and clinical palpation in terms of the area size of LHT. In addition to the precise diagnostic aspects, ultrasound better detects the nature and severity of LHT compared to palpation, allowing greater granularity of LHT (size, distribution, and elasticity), thus giving clinicians the opportunity to give more detailed advice to patients [3, 16]. By visualizing LHT tissue, ultrasound images can encourage changes in injection behavior by revealing areas of tissue disruption, inflammation, and depth of subcutaneous tissue [17]. This has important implications in terms of better implementation of patient education and the subsequent reduction of the incidence of LHT.
Studies related to LHT due to faulty insulin injection techniques have been described in the literature for decades [4]. Unfortunately, most patients do not understand the severity of LHT and prefer to inject insulin in the area associated with LHT instead of the normal injection site because of the reduced pain. Therefore, elucidation of the factors influencing the occurrence of LHT is essential to guide patients on the correct method of insulin injection. Many authors have concluded that LHT is always associated with the following factors: sex, BMI, injection device, whether or not to rotate, injection area, needle length, insulin regimen, and daily total dose of insulin [7]. Among them, correct injection site rotation is the most studied and emphasized method for preventing LHT [18]. However, a number of studies also concluded that the development of LHT is independent of factors such as sex, BMI, and whether needles are used repeatedly [19, 20]. In this study, we measured the subcutaneous fatty hyperplasia tissue using ultrasound and analyzed the main factors affecting the area. The results showed that in addition to the number of years of insulin injection, whether to rotate the injection site and the frequency of needle reuse, the length of the needle was also a factor affecting the size of the hyperplastic tissue, which we speculated might be related to the increase in the damaged area of the subcutaneous tissue when using a longer injection needle. However, the specific factors influencing the onset of development have not yet been elucidated, and further research is needed.
Subcutaneous insulin absorption is one of the key factors affecting glycemic control in insulin-treated diabetic patients. Insulin-induced LHT has been reported to impair normal insulin uptake and affect glycemic control [21]. Almost all early studies reported a significant reduction in insulin uptake (in some cases clearance of radiolabeled insulin at the injection site) and glucose reduction with LHT, and in some cases patients exhibited elevated glycated hemoglobin [22–24]. When subjects with LHT were taught to inject into normal tissues, total daily insulin dose requirements were significantly reduced and glycemic control and variability were improved [25, 26]. In this study design, patients with ultrasound-confirmed LHT were taught to administer equal doses of insulin subcutaneously on LHT and NAT on a non-consecutive 2 d of the week, while the insulin dose was reduced by 10% compared to the original dose to avoid hypoglycemia, in order to assess the effect of LHT on patients' blood glucose fluctuations and insulin dose. The results showed that insulin injections at LHT areas could significantly affect patients' glycemic control and lead to increased blood glucose fluctuations. Therefore, standardized insulin injection education for diabetic patients can help them avoid injecting insulin at LHT areas and can simultaneously achieve the goal of good glycemic management. In addition, the results of this study suggested that when the injection site was changed from fatty hypertrophic tissue to normal tissue, the insulin dose was reduced, avoiding the risk of hypoglycemia on the one hand, and effectively reducing the insulin dosage and mitigating medical costs on the other.
Inevitably, some limitations were present in this study. First, this was a cross-sectional study that only investigated the incidence of LHT in insulin-injected diabetic patients who visited our hospital. Because of the difference in education on injection techniques in different treatment centers, it may not represent the overall incidence of insulin-injected patients. In addition, the small sample size of this study may have introduced errors in the analysis of factors influencing LHT,; thus, more patients need to be included for further analysis. This study is unprecedented in several ways. It provided an innovative summary of the characteristics of LHT under ultrasound and the first detailed comparison of the rate of missed diagnosis between ultrasound and clinical palpation in terms of the area size of LHT.
In summary, LHT is a common comorbidity of long-term insulin therapy in diabetic patients, which not only increases patients' pain and additional financial burden, but also decreases insulin absorption and reduces the efficacy of glycemic control. We strongly recommend training and having experienced health professionals to better identify LHT lesions and apply ultrasound to assist in the diagnosis when necessary. Properly teaching patients the correct way to inject insulin and emphasizing the seriousness of LHT to patients is critical to the long course management of diabetes.