Insulin Autoimmune Syndrome: A Systematic Review

Insulin autoimmune syndrome (IAS) is a rare endocrine disorder characterized by recurrent episodes of severe hypoglycemia, markedly elevated serum insulin, and positive insulin autoantibodies. In recent years, various countries have reported it one after another. It can be seen that we must pay attention to this disease. The diagnosis of IAS is challenging, requiring a careful workup aimed at excluding other causes of hyperinsulinemic hypoglycemia. High levels of insulin autoantibodies are found in patients, and C-peptide is not parallel to insulin, which could be diagnostic. IAS is a self-limiting disease with a good prognosis. Its treatment mainly includes symptomatic supportive treatment, such as adjusting the diet and using acarbose and other drugs to delay the absorption of glucose to prevent hypoglycemia. For patients with severe symptoms, available treatments may include drugs that reduce pancreatic insulin secretion (such as somatostatin and diazoxide), immunosuppressants (glucocorticoids, zaprin, and rituximab), and even plasma exchange to remove autoantibodies from the body. This review provides a comprehensive analysis of the epidemiology, pathogenesis, clinical manifestations, diagnosis and identification, and monitoring and treatment management of IAS.


Introduction
IAS, also known as Hirata disease, was frst described by Hirata in Japan in 1970 [1]. IAS is characterized by recurrent spontaneous hypoglycemia, the presence of insulin autoantibodies in the body, signifcantly elevated serum insulin, and no history of exogenous insulin injections. However, in recent years, it has been found that insulin and its analogs can also induce IAS, and the concept of nonclassical IAS has been proposed [2], so we need to update this view.
Tere is no clear accepted incidence, and current data are based on a comprehensive analysis of case reports. Te age of onset of IAS patients varies greatly. Tere are literature statistics about IAS [3]. From 1994 to May 2017, 142 cases of IAS were reported in the Chinese biomedical literature database, including 62 males and 80 females aged 9-82 years old, with a median age of 46. Among these, 18 were idiopathic IAS. Te results showed that methimazole treatment of Graves' disease was the most common cause of IAS. Other causative drugs included tiopronin, captopril, insulin, dpenicillamine, propranolol, and alpha-sulfur bitter.
IAS is a disease closely related to HLA, specifcally to HLA-DRB1 * 0406, DQB1 * 0302, DQA1 * 0301, DRB1 * 0415 [4], DRB1 * 13: 01 [5], and HLA-DRB1 * 0406, which are most frequently associated with IAS. Te DRB1 * 0406 genotype is more frequent in East Asian patients, including the Japanese, than in Western populations, being rare in Caucasians, which explains why IAS is more common in East Asians and less common in Caucasians. Most Asian patients with IAS have DRB1 * 0406, whereas DRB1 * 0403 occurs in afected Caucasians, which may explain the diference in incidence between these two ethnic groups [6]. It has been reported that Caucasians with the HLA-DRB1 * 0403 allele can develop IAS associated with lipoic acid, indicating that this allele is genetically susceptible to IAS in Caucasians and possibly other populations [6].
Tis review summarizes the number of reported cases of IAS, drugs related to the occurrence of IAS, coexisting diseases, and treatment schemes reported for IAS since IAS was frst described in 1970 (Tables 1-3).

Materials and Methods
We searched PubMed, China National Knowledge Infrastructure, Wan-fang Data Knowledge Service Platform, and China Science and Technology Journal Database to identify studies and reviews published between January 1, 1970, and December 31, 2022, relevant to the scope of this Seminar with the terms "insulin autoimmune syndrome," "IAS," "Hirata disease," "insulin autoantibody," "hyperinsulinemic hypoglycemia," "immunoreactive insulin," and "autoimmune hypoglycemia." Articles were considered regardless of language. We selected references that provided current, evidence-based insight into insulin autoimmune syndrome. Most of the articles selected were published within the past 5 years, although we also included highly referenced, older publications that contributed to new knowledge or understanding of insulin autoimmune syndrome.

Classifcation of IAS.
IAS can be classifed according to diferent perspectives. According to the history of exogenous insulin injection, insulin syndrome is divided into classic IAS and nonclassical IAS [2]. According to the original defnition of IAS, it only occurs in patients without a history of exogenous insulin injection; however, an association with the use of exogenous insulin or insulin analogs has been identifed in recent years [14,15]. Individuals who use insulin glulisine (such as glargine) can have symptoms similar to IAS, usually manifesting as postprandial hypoglycemia, obvious neurological symptoms and changes in their state of consciousness, accompanied by high titers of insulin autoantibodies and serum hyperinsulinemia, so the concept of nonclassical IAS was proposed to distinguish it from the previous classic IAS.

Te Pathogenesis and Pathophysiology of IAS.
It has been reported that more than 50% of patients diagnosed with IAS have previously received drugs containing sulfhydryl groups, which are thought to be related to the chemical and immune responses of insulin molecules and can trigger the production of insulin autoantibodies [37]. Tiol-containing drugs, such as lipoic acid, are a widely used nutritional supplement, taken as an adjunct treatment for diabetic neuropathy and other conditions. Lipoic acid can also increase insulin sensitivity and improve glycemic control in various clinical situations, but it can promote the dissociation of the S-S bond of insulin, expose the peptide to antigen-presenting cells, and stimulate T cells in IAS patients; thus, insulin autoantibodies are formed. Insulin autoantibodies produced in IAS patients are diferent from those caused by exogenous insulin. Insulin antibody (IA) is commonly found in patients receiving insulin treatment. Insulin antibody (IA) usually has low binding capacity and high afnity and rarely causes hypoglycemia, which is  [38]. Approximately 40% of diabetic patients receiving human insulin injections have positive serum insulin antibodies, but these antibodies have little efect on blood glucose [2]. Scatchard analysis showed that insulin autoantibodies in IAS patients have a signifcantly lower afnity constant for insulin and a much stronger binding capacity, showing low afnity/high binding capacity, so autoantibodies could easily bind to insulin [39]. Scatchard analysis of IAS reported that insulin antibodies are polyclonal with a dissociation constant at high-afnity sites that are signifcantly lower than those produced by injected insulin [40]. In Japan, the majority of IAS patients have IgG polyclonal IAAs, whereas IAAs are monoclonal in more than half of reported cases of IAS in non-Asian patients. Although the most common IAA immunoglobulin class is IgG, IgA and IgM have also been reported in IAA cases [41]. Once plasma insulin (antigen) increases to a certain level, the insulin-autoantibody complex becomes unstable and abruptly disintegrates, leading to postprandial hypoglycemia. In addition, some drugs that do not contain sulfhydryl groups, such as clopidogrel, themselves do not contain sulfhydryl groups but become biologically active compounds after being metabolized by cytochrome P450 enzymes, and the active metabolites contain sulfhydryl groups, which can cause IAS. Te mechanism is similar to that of sulfhydryl-containing drugs ( Figure 1).
For IAS caused by insulin analogs, the mechanism is not clear, but it also works through IAA. Te amino acid sequence of insulin analogs is diferent from that of human insulin and can be considered nonself-antigens, especially zinc-mediated insulin, because it is located at the injection site, with a longer residence time and easier uptake by antigen-presenting cells. Te zinc-free insulin analogs are rapidly absorbed into the blood after subcutaneous injection, so they are considered to be less immunogenic than other insulins. Drugs containing sulfhydryl groups or metabolized sulfhydryl groups, as well as insulin analogs, are believed to be immunogenic and lead to the production of insulin autoantibodies. As a matter of fact, even though modern insulin analogs have a low immunogenicity, insulin antibodies may sometimes be detected in patients receiving insulin therapy, but these antibodies are rarely capable of causing hyperglycemia or hypoglycemia. Tis is because the insulin antibodies that develop following exposure to exogenous insulin are more often characterized by a higher afnity and a lower binding capacity against insulin  compared to IAA. As a consequence, they mostly result in smaller antigen-antibody complexes which have a lower spontaneous dissociation rate, and thus, they are unable to produce signifcant glycemic fuctuations. Nevertheless, insulin antibodies developing after the administration of exogenous insulin may seldom present with features similar to those of IAA, such as a high binding capacity and low afnity, thus resulting in glycemic instability [42]. However, some drugs that do not contain sulfhydryl groups, such as loxoprofen sodium, can also lead to the production of insulin autoantibodies, but there is no relevant literature on the possible mechanism.
In patients with this low-afnity/high-binding antibody, food-stimulated pancreatic insulin rapidly binds to insulin autoantibodies after eating, and this binding reduces insulin utilization by receptors in the liver and peripheral tissues, masking the biological activity of insulin and leading to postprandial hyperglycemia, which further stimulates insulin secretion from the pancreas [43]. Dozio et al. [43] investigated the mechanism of hypoglycemia by performing 125I-labeled insulin scintigraphy in a patient with IAS. Following intravenous administration of 125I-labeled insulin, the patient showed sustained labeled insulin activity in the blood, with no uptake of labeled hormones in the liver or kidneys. In the late postprandial period, due to the low afnity of insulin autoantibodies to insulin, excess insulin does not bind to the insulin autoantibodies, and the free insulin exerts its inherent hypoglycemic efect, resulting in a sharp drop in blood glucose and late postprandial hypoglycemia.
In addition, some patients mainly present with fasting or early morning hypoglycemia, which is caused by the separation of insulin and insulin antibodies due to changes in the internal environment during the night (which may be related to decreased insulin antibody afnity). Insulin antibodies become saturated with insulin during the day, which means that fewer antibodies are available to bind to insulin in the middle of the night [2].

Clinical Manifestations of IAS.
Hypoglycemia or alternating episodes of hypoglycemia and hyperglycemia: patients often show the typical Whipple triad, that is, 1. symptoms and signs of hypoglycemia, including autonomic hypoglycemia symptoms (tremor, palpitation, anxiety, sweating, hunger, and sensory abnormalities, which are largely caused by sympathetic activation) and cerebral neuronal hypoglycemia symptoms (mainly including cognitive impairment, behavioral changes, psychomotor abnormalities, and seizures and coma when their blood glucose concentration is lower), 2. blood glucose <2.8 mmol/l during an attack, and 3. the symptoms will be relieved rapidly after administering glucose-increasing drugs. According to previous case reports, approximately 42% of patients showed postprandial delayed hypoglycemia, 31% had fasting hypoglycemia, and 24% had both postprandial and fasting hypoglycemia [44,45]. As mentioned previously, the occurrence of hyperglycemia and postprandial delayed hypoglycemia is mainly caused by the binding and dissociation of insulin autoantibodies and insulin. Continuous blood glucose monitoring system data confrmed that IAS alternates between postprandial hyperglycemia and postprandial hypoglycemia   [46]. A few cases of insulin autoimmunity manifested as hypoglycemia after repeated diabetic ketoacidosis [47]. In addition, some patients with recurrent hypoglycemia and a long course of the disease may gain weight due to frequent eating [48,49].

IAS-Related
Tests. At present, the most commonly used test for diagnosing IAS is IAA, but a commercial kit for detecting IAA has not been widely used [49]. Insulin autoantibodies in IAS patients are usually IgG class immunoglobulins, but IAA can also belong to other classes (such as IgA and IgM). Te kits on the market usually only recognize the IgG class, so they sometimes give false negative results; thus, a negative IAA test does not completely rule out IAS. To avoid misleading results, it is critical that IAA assays detect all immunoglobulin classes and subclasses [41]. Uchigata et al. [25] suggested that the measurement of insulin may cause erroneous results due to the interference of antibodies with the measurement results. By adding PEG or ultrafltration, if the insulin is combined with antibodies, the heavy protein molecules are precipitated, and free insulin can be measured in the supernatant. Serum-free insulin levels are detected after polyethylene glycol precipitation of IAA, and the free insulin is separated from antibody-bound insulin; in suspected cases of IAS, a signifcant diference between total serum insulin and free insulin strongly suggests IAS [20].
Basu and John [50] reported the cases of 7 white IAS patients and found that during hypoglycemia, the concentrations of insulin, proinsulin, and C-peptide greatly exceeded those observed in insulinoma patients, but they were falsely elevated due to the interference of autoantibodies. Tis confrmed the hypothesis that autoantibody interference in immunoassays leads to excessive insulin concentrations by measuring free insulin after a mixed meal test.
Polyethylene glycol precipitation and gel chromatography separation methods can be used to identify whether there are macromolecular immune complexes bound to insulins, especially for patients with negative insulin autoantibodies. Polyethylene glycol can precipitate all immunoglobulin IAA [41], but it has little efect on small molecular proteins such as insulin. If there is an insulininsulin autoantibody immune complex in the serum, it will be precipitated by polyethylene glycol, and the insulin level measured after precipitation will decrease. Gel chromatography can separate proteins according to their molecular weight, and macromolecular insulin-insulin autoantibody complexes will be eluted before the smaller molecules of free insulin, showing high levels of "insulin" (actually insulininsulin autoantibody complexes) [51]. Te polyethylene glycol precipitation method is an inexpensive laboratory method that can be achieved by virtually any laboratory, with the advantages of a simple operation, short time consumption, and low cost, and it can be used as a primary screening experiment. However, it should be noted that the polyethylene glycol method is susceptible to the interference of macromolecular proteins and temperature, which afects its specifcity. Te gel chromatography separation method is relatively complicated, time-consuming, and expensive (it needs to measure insulin and adiponectin in multiple collection tubes), so it is not suitable for primary screening. Conditional laboratories can use this method as a confrmatory test [41].
Insulin and C-peptide are cosecreted into the portal circulatory system in an equimolar ratio by pancreatic beta cells. Insulin is mainly cleared by the liver, C-peptide is mainly metabolized by the kidney, and the metabolism of Cpeptide is signifcantly slower, so the half-lives of these two are 5-10 minutes and 30-35 minutes, respectively. Tus, the molar ratio of insulin to C-peptide is generally less than 1, although insulin and C-peptide are secreted in equal proportions. In general, there are two situations that result in a molar ratio of insulin to C-peptide greater than 1. One is in patients with IAS. Second, during artifcial hypoglycemia caused by exogenous insulin, the insulin concentration increases, and the C-peptide level is inhibited so that the ratio is greater than 1 [52]. However, a study that reviewed 16 patients with IAS pointed out the limitations of the insulin to C-peptide molar ratio; 9 of the 16 patients had an insulin to C-peptide molar ratio >1, while 6 patients had insulin to C-peptide molar ratio. Te molar ratio to Cpeptide is < 1, which indicates that the molar ratio of insulin to C-peptide can only be used for the auxiliary diagnosis of IAS [53] (Table 4).
It is generally believed that in patients with IAS, the typical monophasic pattern of hyperinsulinemia measured by the oral glucose tolerance test (OGTT) of insulin secretion kinetics is evident; however, there are also some patients whose insulin secretion kinetics by the OGTT are shown as biphasic insulin secretion kinetics distinct from typical IAS. One study reported a pair of sisters who both sufered from IAS, and their insulin secretion kinetics measured by the OGTT showed a biphasic insulin secretion kinetic pattern [40]. Compared with 32 healthy adults, IAS patients had signifcantly lower fasting blood glucose levels than controls. However, the oral glucose tolerance test (OGTT) showed that all patients with IAS had impaired glucose tolerance or diabetes, so their OGTT 2 h blood glucose level was signifcantly higher than that of the control group [45]. On the OGTT, some patients showed a diabetic pattern, while others showed impaired glucose tolerance [54].
Hyperglycated hemoglobin levels are common in patients with IAS, but there are some patients whose glycated hemoglobin is within the normal range, and the detection of glycated hemoglobin is of little signifcance for the diagnosis of IAS [41].
Some studies have analyzed the clinical indicators of IAS patients and normal healthy subjects [54]: Glycated albumin (GA) levels and GA/HbA1c ratios in IAS patients were signifcantly higher than those in the control group, but there was no signifcant diference in HbA1c levels between the two groups. In the case of spontaneous remission of IAS, there was a signifcant correlation between anti-insulin antibodies and GA but not HbA1c. With the improvement of clinical symptoms, the anti-insulin antibody, GA, and GA/HbA1c ratio of 3 IAS patients decreased, but HbA1c International Journal of Endocrinology International Journal of Endocrinology did not change signifcantly. Tese results suggest that GA and the GA/HbA1c ratio are useful indicators for determining the level of disease activity in patients with IAS. Glycated albumin (GA), on the other hand, is an intermediate indicator of glycemic control, refecting fuctuations in blood sugar, as well as average blood sugar levels. In addition, the GA/HbA1c ratio is an indicator refecting blood sugar fuctuations. Trough continuous glucose monitoring (CGM) analysis, it has been demonstrated that patients with IAS have increased glycemic excursions as they develop postprandial hyperglycemia in addition to fasting hypoglycemia. Te purpose of the 72-hour fasting test is to provoke hypoglycemia in the absence of food. Normal individuals do not develop symptomatic hypoglycemia after prolonged fasting due to hormone-mediated increases in glucose production. Prolonged fasting can lead to hypoglycemia only when there is a defcit in the ability to maintain normoglycemia, such as too much insulin. Te 72-hour fasting test is a standard test for the diagnosis of insulinoma [55] and can be used to diferentiate insulinoma from IAS. In general, the IAS 72-hour fasting test is generally free of hypoglycemia, and there are case reports of no spontaneous hypoglycemia in patients undergoing the 72-hour fasting test. However, after the 72-hour fasting test, reactive symptomatic hypoglycemia occurred 12 hours after eating. Some patients with IAS may also have hypoglycemia during the 72-hour fasting test, so the 72-hour fasting test cannot completely distinguish IAS from insulinoma. One study analyzed the 72-hour fasting test of 74 insulinomas, and all patients with insulinoma developed hypoglycemia [52].
A continuous glucose monitoring system continuously converts the glucose level present in the interstitial tissue into an electrical signal whose intensity is proportional to the glucose content. Te sensor measures the tissue fuid glucose concentration every 5 minutes on average. Continuous glucose monitoring systems can efectively monitor diet and treatment measures [53]. Continuous blood glucose testing showed that blood glucose levels worsened after glucocorticoid treatment, and the hyperglycemic state associated with hypoglycemia persisted longer. Glucosidase inhibitors and plasma exchange are more efective in limiting glucose intake than glucocorticoids or diet alone. Te use of continuous glucose monitoring systems has also demonstrated the efectiveness of plasma exchange in treating insulin autoimmune symptoms by normalizing blood glucose and antibody levels, although it is not a curative treatment. Te use of continuous glucose monitoring systems provides a way to precisely assess the efcacy of diferent drugs [56].
Notably, some patients are positive for antibodies, anti-dsDNA, and rheumatoid factor, but whether they are associated with IAS requires further investigation [43].
3.5. Diferential Diagnosis. IAS needs to be distinguished from insulinoma. In patients with insulinoma, hypoglycemia often occurs in the fasting state, while in IAS, it often occurs repeatedly at night and in the early morning. A fasting test is a method of diferential diagnosis. Te insulin concentration level of insulinoma is generally less than 1000 mu/ml, and the increase in insulin concentration is synchronized with the increase in C-peptide levels, while the insulin concentration of IAS patients is often greater than 1000 mu/ml [3]. Te blood glucose level of IAS fuctuates widely. Hypoglycemia and hyperglycemia can occur alternately, while insulinoma generally does not have hyperglycemia. IAA is the key to diferentiation. Most IAS is positive, and a few are negative, but the IAA level of insulinoma is always negative. Abdominal computed tomography (CT) is also an important examination method to distinguish IAS and insulinoma. Generally, CT is not abnormal in patients with IAS, while patients with insulinoma often have positive fndings. However, it should be noted that a small number of IAS patients are complicated with pancreatic space-occupying lesions, which are difcult to distinguish and require special attention. A correct diagnosis is very important because it can prevent patients with hypoglycemia from undergoing unnecessary pancreatic surgery.
IAS must also be distinguished from hypoglycemia caused by insulin receptor antibodies, also known as type B insulin resistance. In these cases, antibodies cause hypoglycemia through the direct activation of insulin receptors. It is characterized by obvious acanthosis nigricans, accompanied by severe hyperglycemia and other autoimmune diseases [57].
IAS also needs to be distinguished from hypoglycemia caused by hypoglycemic drugs or insulin and its analogs. In diabetic patients (type 1 and type 2 diabetes), IAS can also occur. Terefore, it is particularly important to identify hypoglycemia caused by these two causes. Another diferential diagnosis of IAS is hypoglycemia caused by advanced dumping syndrome [58].
For patients with hypoglycemia and a history of taking drugs that induce IAS, IAS should be considered as a differential diagnosis. High concentrations of autoantibodies, C-peptide, and insulin imbalance are highly suspicious for IAS.
It is mentioned in the literature that the insulin autoantibodies will disappear on their own within a few months to several years, which is one of the pieces of evidence that IAS is self-limiting. Hirata and Uchigata reported that most hypoglycemia lasts less than 1 month, with an average of 3-6 months [54]. A study found that among 73 patients with IAS, 5 patients had mild hypoglycemia that lasted for more than 1 year. Some patients can avoid or reduce the occurrence of hypoglycemia symptoms simply by discontinuing International Journal of Endocrinology  8 International Journal of Endocrinology IAS-related drugs or discontinuing other related drugs, eating small meals, and avoiding monosaccharide intake. Tis is the frst-line treatment for IAS. It has been reported that although the hypoglycemia symptoms disappear after a few weeks or months, the antibodies may persist for several years, and thus, the mechanism behind the disappearance or signifcant reduction of hypoglycemia is still unclear. In some obese patients with IAS, the improvement in hypoglycemic episodes with weight loss may be due to a reduction in insulin resistance resulting in a lower postprandial insulin peak [63]. An additional treatment strategy for IASs is to bufer the efects of autoantibodies that bind to endogenous insulin and reduce the formation of complexes with endogenous insulin. Acarbose and voglibose have inhibitory efects on intestinal α-glucosidase; they can delay the absorption of postprandial carbohydrates, make the blood sugar rise more slowly, reduce the stimulation of blood sugar to the pancreas, and trigger the production of insulin. Te secretion of insulin decreases, avoiding the combination of a large amount of insulin with insulin autoantibodies, and improves the symptoms of postprandial hypoglycemia in patients with the autoimmune syndrome. In addition, a study [64] showed that cornstarch delays absorption and has been used to treat glycogen storage disorders in patients with hypoglycemia and unstable glycemic control in patients with type 1 diabetes. According to this theoretical basis, IAS is treated by dietary management with cornstarch. After cornstarch is given, the symptoms of hypoglycemia at night disappear, indicating that cornstarch treatment is efective, and its mechanism is similar to that of α-glucosidase inhibitors to delay carbohydrate absorption. However, this is the frst and only case of cornstarch therapy for the treatment of IAS, and the possibility of spontaneous remission cannot be completely ruled out, but it suggests the potential usefulness of cornstarch therapy in preventing hypoglycemia in patients with IAS.
Glucocorticoid therapy can be used for patients with IAS that cannot be controlled by discontinuation of IAS-related drugs, dietary management, and the use of alpha-glucosidase inhibitors. Many studies have mentioned that in cases where the above two methods cannot relieve the hypoglycemia, the use of glucocorticoids can efectively reduce the frequency and severity of hypoglycemia, and it has a good efect in reducing insulin autoantibodies in patients. Te most commonly used glucocorticoid is methylprednisolone. A study in Japan [57] showed that corticosteroid treatment reduced the number of insulin receptor binding sites and avoided hypoglycemic episodes, suggesting the efectiveness of corticosteroids in the treatment of IAS. Among other second-line regimens, immunosuppressants (azathioprine and 6-mercaptopurine), monoclonal antibodies (rituximab), plasma exchange, and strategies to reduce insulin release (somatostatin analogs, pancreatectomy) have shown some efcacy in the management of IAS. Rituximab reduces IAAs and improves hypoglycemia.
Partial pancreatectomy may be feasible in refractory patients with frequent episodes of hypoglycemia [53] but is currently rarely used in clinical practice. In a patient diagnosed with IAS, the patient developed metabolic acidosis, and the symptoms of hypoglycemia disappeared after the administration of sodium bicarbonate, but its mechanism and efcacy still need to be confrmed by a large number of studies.
IAS is mostly a self-limiting disease with a good prognosis. In the absence of other serious complications, after removing the triggers and using immunosuppressive drugs or drugs that delay glucose absorption, the symptoms mostly disappear after a few months, and the outcome is good.

Conclusion
IAS is a rare endocrine disease, but in Japan, IAS is the third leading cause of spontaneous hypoglycemia, and the incidence of this disease is increasing. An increasing number of countries has reported this disease one after another. Its increasing incidence is not just due to improvements in detection methods; the widespread use of drugs is also a factor that cannot be ignored. Te current drug spectrum related to IAS is expanding, which requires us to pay more attention to it. For this disease, insufcient laboratory examinations and other auxiliary examinations can easily cause misdiagnosis and missed diagnosis, which suggests that we need to develop more efective detection methods. Tere is no standardization of the treatment plan at present, and additional research is needed to unify and develop an efective treatment plan. Tese are problems that urgently need to be solved.

Data Availability
Te data that support the fndings of this study can be obtained from the corresponding author upon reasonable request.

Conflicts of Interest
Te authors declare that they have no conficts of interest.