Introduction

In recent years, immune checkpoint inhibitor (ICI) therapy has emerged as a promising approach in cancer treatment. This breakthrough approach leverages the body’s immune system to fight cancerous tumors, providing patients with valuable therapeutic alternatives and improved survival prospects [1]. Initially employed in the treatment of malignant melanoma and lung cancer, this technique involves the administration of monoclonal antibodies that target specific cell proteins such as cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and its ligand (PD-L1). Therefore, T cell activation against neoplasms is induced [2, 3]. However, alongside its benefits, the therapy comes with a range of adverse effects, with thyroid disorders being among the most prevalent endocrine complications. Thyroid dysfunction manifests with a wide clinical spectrum encompassing thyroiditis, both hypo- and thyrotoxicosis, Graves’ disease [4]. Its pathophysiological basis is considered to be destructive thyroiditis induced by a T cell-mediated acute autoimmune response [1, 5,6,7,8,9]. However, studies consistently highlight the role of autoantibodies against thyroglobulin (Tg), thyroid peroxidase (TPO) and thyroid stimulating hormone (TSH) receptor and even the role of cytokines in the pathogenesis of the disease [10, 11]. Therefore, laboratory tests involving TSH, free thyroxine (fT4), and antibody measurements carry immense importance not only in accurate diagnosis, but also as check-up prior to and during ICI therapy [12]. ICI-induced thyroidopathy ranges in clinical presentation from asymptomatic cases to severe manifestations and death [13]. Addressing these complications necessitates the prompt diagnosis of the thyroid disorder, along with the implementation of therapeutic strategies and drug dosages, tailored to the clinical manifestations and their severity. In essence, close monitoring and collaboration between oncologists and endocrinologists is required [13,14,15].

Pathogenesis

Thyroid dysfunction is the most common endocrine adverse effect associated with ICI therapy. Most studies report two patterns of ICI-related thyroid dysfunction: thyrotoxicosis followed by hypothyroidism and isolated hypothyroidism. However, the pathophysiological basis that appears to be common is destructive thyroiditis [5,6,7, 9]. The underlying pathophysiology is considered to be an immune-mediated acute inflammation followed by destruction of the thyroid gland. ICI therapy induces autoimmune side effects through T cell activation and is characterized by intra-thyroidal predominance of CD8+ and CD4-CD8- T lymphocytes [1, 8]. In a case report of a nivolumab-related hypothyroidism, the anti-PD-L1 therapy suppressed the inhibitory PD-1/PD-L1 signals on follicular helper T cells (Th), leading to increased proliferation and subsequent overproduction of thyroid autoantibodies [16].

In accordance with the above, recent studies suggest that autoantibodies against thyroid peroxidase (TPOAb) and thyroglobulin (TgAb) have been found elevated at baseline in some patients who develop thyroid dysfunction after ICI immunotherapy. TPOAb and TgAb may be present at baseline prior to or may develop after ICI therapy. Maekura et al. studied the levels of TPOAb and TgAb in 53 patients treated with nivolumab for non-small cell lung cancer (NSCLC) in an attempt to predict the occurrence of hypothyroidism [17]. Among the nine patients who tested positive for TPOAb at baseline, 44% (4 out of 9) developed ICI-related hypothyroidism, compared to 2% (1 out of 44) in those who were TPO Ab negative at baseline. Among the nine patients who had positive TgAb at baseline, 56% (5 out of 9) developed ICI-related hypothyroidism, while no one out of the 44 patients who were TgAb negative at baseline experienced the same. In the Osorio et al. study, TPOAb and TgAb levels were examined not only at baseline, but also during pembrolizumab (anti-PD-1) treatment [18]. Additionally, according to the study of Muir et al. anti-thyroid antibodies basal positivity is associated with increased possibility of developing a thyroid disorder. The risk of overt thyrotoxicosis is higher when the title of TPOAb or/and TgAb is remarkably elevated or when there is a newfound thyroid antibody positivity [19]. The correlation between basal positivity of TPOAb and TgAb and high risk of thyroid dysfunction after the initiation of ICIs therapy is also supported by the study of Zhou et al. [20]. Reportedly, the development of positive thyroid autoantibodies after initiation of ICI therapy is associated with higher risk of ICI-induced thyroid dysfunction.

In similar studies, stimulatory autoantibodies against TSH receptor (TRAb) or thyroid-stimulating immunoglobulin (TSI) predominantly found negative in the majority of cases. Case reports indicate that ICI therapy-induced thyroid dysfunction may impact and abolish the thyroid stimulating effect of TSI. Notably, destructive thyroiditis may coexist with Graves’ disease in a minority of cases, as suggested by TRAb positivity [10, 11].

Individual genetic susceptibility to thyroid dysfunction also plays an important role. More specifically, thyroid dysfunction has been shown to be associated with overexpression of Human Leukocyte Antigen DR-isotype (HLA-DR). Treatment with ICI therapy can change HLA-DR expression, increasing T cell activation and leading to thyroid autoimmune disease. Delivanis et al. conducted a study examining healthy volunteers, patients with autoimmune thyroiditis, and individuals with pembrolizumab-induced thyroiditis [21]. The study revealed an elevated count of CD56 + CD16+ Natural Killer (NK) cells and increased surface HLA DR expression on inflammatory intermediate CD14 + /CD16+ monocytes in patients with pembrolizumab-related thyroiditis. Comparing the PD-1 levels on peripheral T-cells among the three groups, they were undetectable on the surface of T-cells in those with pembrolizumab-induced thyroiditis, while they were comparable between healthy volunteers and patients with autoimmune thyroiditis. Thus, macrophage activation through up-regulation of HLA-DR may be a possible mechanism of pembrolizumab-induced thyroiditis. In addition to T and B lymphocytes, various cytokines play an essential role in the development of thyroid disorders. First and foremost, elevated interleukin (IL)-2 levels facilitate the binding between HLA-II and thyroid cell autoantigen, leading to stimulation of CD8+ cytotoxic T lymphocytes (CTL) and subsequent thyroid cell death. According to recent studies PD-L1 therapy increases CD4 + Th1 and therefore the expression of interferon gamma (IFN-γ) and IL-2, which leads to thyroid cell death. Kurimoto et al. measured the changes of various cytokines before and after ICIs treatment and identified that an increase in IL-2 and a decrease in granulocyte colony-stimulating factor (G-CSF) appeared to be associated with thyroid immune-related adverse events (irAEs) [22]. Regulatory T cells (Tregs) enhance the response to anti-PD-L1 therapy by releasing cytokine IL-10. Conversely, Treg inhibition through ICI therapy is implicated in the development of autoimmune thyroid diseases [23] (Table 1).

Table 1 Thyroid dysfunction linked with particular ICI-therapy for specific cancer subtypes
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Clinical presentation

Clinical diagnosis of thyroid toxicity is challenging, as patients may not exhibit any noticeable symptom or sign or present with non-specific symptoms [24]. However, due to the accessibility of thyroid function screening, thyroid disorders are frequently identified at an early stage, even when patients do not display typical symptoms. The spectrum of thyroid disorders induced by ICIs includes thyroiditis, hypothyroidism, Grave’s disease and thyrotoxicosis [6]. Most cases involve thyroiditis processing to hypothyroidism [4]. Although hypothyroidism is typically permanent in most cases, it is currently impossible to determine the ratio of transient hypothyroidism compared to permanent cases [25, 26].

For the majority of symptomatic patients, the first manifestation is thyrotoxicosis [6]. Thyrotoxicosis usually presents with weight loss, palpitation, tremors, anxiety, fatigue and sweating [27]. In addition, increased perspiration, heat intolerance, hyperdefecation and generally increased metabolic activity are clinical manifestations that should raise suspicion of thyrotoxicosis [28, 29]. Physical examination sometimes reveals increased heart race and warm skin [13]. Atrial fibrillation may be seen, especially in older patients [30]. Initial presentations of overt or subclinical thyrotoxicosis typically resolve to euthyroidism or hypothyroidism within several weeks to months.

Primary hypothyroidism is a thyroid adverse effect that is more commonly noticed in patients treated with PD-1 inhibitors [31]. Hypothyroidism can be detected during routine lab monitoring in asymptomatic patients or clinically presents with the typical symptoms such as weight gain, depression, profound fatigue, alopecia, cold intolerance, constipation, dry skin, bradycardia, periorbital edema and tongue swelling [4, 29, 30]. While most cases are mild to moderate, untreated severe hypothyroidism can lead to myxedema coma, decreased mental status and often hypothermia [30].

Graves’ disease induced by ICIs is primarily associated with CTLA‐4 gene polymorphisms [32]. While it is extremely rare, cases have been reported. It appears usually at the beginning of the treatment. The presence of thyroid eye disease increases the possibility of Graves’ disease, while signs such as orbitopathy or a large goiter enhance its diagnosis [27, 33].

Epidemiology

Thyroid disorders may occur even after the first single therapeutic dose of ICI therapy [6, 13]. The median time of the onset is 6–10 weeks after the initiation, but it may happen as early as 7 days post therapy initiation and as late as 3 years [6, 13, 21, 33,34,35]. Thyroid dysfunction is mainly associated with anti-PD-1 monotherapy and its combination with PD-L1 or/and anti-CTLA-4 therapy rather than with anti-CTLA-4 or anti-PD-L1 monotherapy [19, 27, 36]. CTLA-4 inhibitors are mostly correlated with the possibility of developing hypothyroidism, while PD-1/PD-L1 inhibitors can lead to thyrotoxicosis and hypothyroidism [19]. More specifically, thyrotoxicosis induced by anti-CTLA-4 affects 0.2–1.7% of the patients, while thyrotoxicosis induced by anti-PD-1 affects o.6-3.7% of the patients. ICIs combination is responsible for 8–11% of the cases of thyrotoxicosis. Hypothyroidism is induced by CTLA-4 inhibitors in 2.5–5.2% of the cases, by PD-1/PD-L1 inhibitors in 3.9-8.5% and by the combination of anti-CTLA-4 and anti-PD-1 in 10.2–16.4% of the patients [37]. Various factors, including cancer subtype, the ICI dosage, and age, influence the risk of thyroid ICI side effects, with current conflicting results regarding age and sex hormones [38, 39]. ICIs induce thyroid dysfunction more frequently in women than in men [28].

Thyroid disorders induced by ICIs and cancer prognosis

Several studies have shown that cancer patients undergoing ICI treatment who develop immune-related adverse effects (irAEs), particularly thyroid dysfunction, often exhibit improved prognosis. Combining the results of the retrospective studies conducted by Prather et al. and Trudu et al., it is suggested that lung cancer patients experiencing irAEs had longer progression-free survival (PFS) and improved overall survival compared to those without these side effects. This implies that irAEs may serve as potential indicators of enhanced treatment efficacy [40, 41]. Similarly, Zheng et al. reported that 47% of hepatocellular carcinoma (HCC) patients treated with anti-PD-1 therapy developed thyroid dysfunction [42]. The survival rates showed no significant difference between the group with normal thyroid function and the one with abnormal thyroid function [42]. Han-Sang Baek also revealed that individuals experiencing with irAEs, in particular hypothyroidism, demonstrated a more favorable prognosis compared to those without irAEs. This association remained irrespective of factors such as age, sex, type of ICI used, and cancer type [43]. Studies by Kotwal et al. and Lima Ferreira et al. also observed improved survival in patients with thyroid dysfunction across different cancer types and ICI therapies [44, 45]. However, these studies did not distinguish between different types of thyroid dysfunction. In contrast to these findings, a case study highlighted a lung cancer patient who developed ICI-related thyroid dysfunction, leading to tumor progression and preventing surgical intervention. This suggests that thyroid dysfunction does not uniformly indicate a better response to ICI treatments [43, 46]. This becomes more intricate as studies propose that thyrotoxicosis could potentially exacerbate cancer prognosis [47]. Von Itzstein et al. noted poorer outcomes in patients with pre-existing thyroid dysfunction but also observed that initiating levothyroxine after beginning ICI treatment improved overall survival [48]. This indicates that pre-existing thyroid problems might negatively impact the effectiveness of ICI therapy and should be managed adequately before starting ICI treatment.

Laboratory and imaging evaluation

The evaluation of TSH and fT4 is recommended before the initiation of ICI therapy, in order to rule out the possibility of any preexisting thyroid disorder [12]. Thyroid function screening, involving TSH and fT4 measurements, should be conducted every 4–6 weeks, or more frequently, if necessary, for all the patients undergoing ICIs treatment [4, 12, 35]. Monitoring of the patients on ICIs immunotherapy should occur 4–6 weeks after the completion of the last cycle [49]. Some clinicians suggest the measure of TSH and fT4 before every circle of treatment [14, 35].

ICI-induced hypothyroidism is characterized by decreased levels of free thyroxine (fT4) [28]. The assessment of TSH is a more sensitive test [35]. Elevated TSH with low or low-to-normal fT4 set the diagnosis of primary hypothyroidism, while low or inappropriately low-to-mid-normal TSH levels with low fT4 indicate secondary/central hypothyroidism attributed to pituitary disorder, such as hypophysitis [12, 30, 50, 51]. In this case, measuring cortisol is indicated to assess for adrenal insufficiency [30]. Primary hypothyroidism may be subclinical. Subclinical hypothyroidism is diagnosed when TSH is elevated but below 10 mIU/mL accompanied by a normal free T4 level [4]. For cases of hypothyroidism, including TPO-antibody testing is prudent as it indicates an autoimmune origin [34].

Overt thyrotoxicosis is characterized by suppressed TSH serum levels and elevated fT4 and/or total triiodothyronine (TT3), while subclinical thyrotoxicosis is defined as suppressed TSH with normal fT4 and TT3 serum levels [9]. Due to the potential process to subclinical hypothyroidism, a repeat thyroid function evaluation test should be performed 6 weeks after the initial diagnosis [4]. Guidelines recommend TSH receptor-antibody testing in case of thyrotoxicosis [34].

Suspecting Graves’ disease is raised when thyroid hormones (T4 and T3) levels are significantly high, initial symptoms are prominent, thyrotoxic manifestations persist for over 6 weeks and other characteristic signs, including orbitopathy or a large goiter, are present. For those patients, the diagnosis is established by the positivity TSI and/or thyrotropin receptor antibodies [12]. In contrast to screening of thyroid function, the screening for TPO-antibodies before the initiation of ICIs is not recommended [34]. Additionally, since some cases of Graves’ disease have been reported with normal levels of TSH receptor antibodies, ultrasonography and scintigraphy/gamma scan are indicated [12, 24]. Doppler ultrasound in Graves’ disease typically reveals increased blood flow, presenting as high vascularity in the thyroid gland [27]. Thyroid uptake tests are recommended for patients with high likelihood of developing Grave’s disease and who have not been exposed to intravenous CT contrast for at least 1 month, as this exposure may reduce thyroid iodine uptake [6, 27]. Radioactive iodine uptake is a valuable tool in differentiating Graves’ disease from other causes of thyrotoxicosis such as destructive thyroiditis [51]. It involves administering a diagnostic dose of iodine-123 orally, followed by measuring its absorption by the thyroid gland either 6 or 24 h later. Graves’ disease is characterized by high, diffuse, homogenous iodine uptake and elevated titers of TRAbs, while destructive thyroiditis is associated with low iodine uptake and the presence, though not elevated, titers of TRAb [15, 24, 27, 50]. Characteristic ultrasonic indicators of ICI-induced destructive thyroiditis include widespread thyroid gland enlargement, decreased internal blood flow, and reduced internal echogenicity (Table 2).

Table 2 Clinical presentation, laboratory and imaging evaluation of thyroid disorders
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Treatment

Multiple organizations have proposed various treatment approaches for thyroid immune-related adverse events (irAEs) caused by ICIs, such as American Society of Clinical Oncology (ASCO), National Comprehensive Cancer Network (NCCN), Society for Immunotherapy of Cancer (SITC) and European Society for Medical Oncology (ESMO) (Table 3). These guidelines demonstrate a high level of agreement [13, 52]. The severity of each side effect is classified into five grades based on the Common Terminology Criteria for Adverse Effects (CTCAE) established by the National Cancer Institute (NCI) of the National Institutes of Health (NIH).

Table 3 Guidelines for ICI-induced thyroid disorders’ treatment
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In cases of hypothyroidism, asymptomatic patients with mild thyroidopathy (TSH 4–10 mIU/l), normal FT4 (grade 1) can continue ICI therapy, with regular TSH monitoring every 4–6 weeks. Ιn patients having moderate thyroidopathy (TSH over 10 mIU/l or TSH 4–10 mIU/l) with low FT4, with or without symptoms, such as constipation, cold intolerance, fatigue, disturbances in the menstrual cycle, arthralgias, myopathy, pale and/or dry skin, thin brittle hair or fingernails, depression signs, weight gain, weakness, etc (grade 2), ICI therapy should be ceased for a while, until the irAEs subside [13]. These patients should start with a replacement dose of approximately 1,3 μg/kg/day levothyroxine. Special attention should be paid to the elderly patients or those with cardiovascular compromise, beginning with a lower daily dose of 25–50 μg and gradually increasing it or simply reducing the default dose by approximately 10%, in order to avoid the risk of thyrotoxicosis [13, 14]. TSH should be assessed every 6 weeks to determine the appropriate dose, whereas FT4 can be evaluated to certify the adequacy of the default dose [13, 53]. Patients with severe thyroidopathy and symptoms like puffiness of face, low temperature, low heart rate, slow speech (grade 3) are managed similarly to patients in grade 2 with the only difference that expert opinion from an endocrinologist is necessary, while at previous grades just recommended. Patients with life-threatening thyroidopathy, exhibiting severe symptoms that could lead to death (grade 4), are treated as mentioned above [13]. However, physicians remain particularly vigilant for signs of myxedema, such as progressive weakness, stupor, hypothermia, hypoventilation, hypoglycemia and hyponatremia. In such cases, hospitalization for intravenous treatment is necessary. Levothyroxine treatment is recommended until the TSH levels are restored to normal. Adrenal insufficiency should be ruled out if suspected [14, 51].

If the physician suspects an underlying thyrotoxicosis, patients should undergo thorough monitoring to exclude the possibility of destructive thyroiditis, which requires a distinct management approach. In such instances, due to their potential to turn to hypothyroidism, it is prudent to avoid the use of I-131 [13]. For cases of thyrotoxicosis, individuals with mild thyroidopathy (TSH less than 0.4 mIU/l), whether symptomatic or asymptomatic (grade 1), can proceed with ICIs therapy, with regular monitoring of TSH, FT4, T3 every 2–3 weeks [13, 53]. Patients with moderate thyroidopathy, low TSH and moderate symptoms, such as heat intolerance, attention deficit disorder, gastrointestinal (GI) hypermotility, insomnia, hair loss, tremor, anxiety etc., (grade 2) should temporarily discontinue ICIs until the resolution of adverse effects and simultaneously initiate a beta blocker therapy [13, 53]. Methimazole or propylthiouracil (PTU) may be administered if thyrotoxicosis persists for over 6 weeks in these patients [13, 53]. In case of persistent thyrotoxicosis, it is also prudent to investigate Graves’ disease (TSH receptor autoantibodies-TRAb). TSH, FT4, T3 should be measured at these patients every 3–4 weeks and the expert’s care (endocrinologist) should be provided [53]. The management of patients with severe thyroidopathy and severe symptoms like tachycardia and palpitations (grade 3) follows the same approach as for the previous stage. The first line treatment remains beta blocker and PTU/methimazole [13]. Corticosteroids are also acceptable at this stage, despite the lack of strong evidence for their efficacy [53]. Patients with life-threatening thyroidopathy and symptoms severe enough to potentially lead to death (grade 4) are treated similarly, with the distinction that hospitalization may be warranted, when suspecting an upcoming thyroid storm [13]. Furthermore, a common and widely accepted approach at this point involves the administration of 1–2 mg/kg/d or equivalent prednisone during a brief titrating period of 1–2 weeks. Saturated solution of potassium iodide or PTU/methimazole can also be used [53].

In case of thyroid storm, it is recommended to administer a non-selective beta blocker, typically propranolol, at doses of 40 to 80 mg every four to six hours, high dose glucocorticoids, to prevent the peripheral conversion of T4 to T3, and a starting dose of 500 to 1000 mg of propylthiouracil (PTU) continuing with a subsequent dose of 250 mg every four hours [13, 14]. Both PTU and methimazole block the production of thyroid hormones. Nonetheless, PTU is preferred over methimazole in this case, because of its additional effect of blocking peripheral conversion of T4 to T3. Immunotherapy can be continued only if the patient is asymptomatic, while TSH and FT4 levels should be monitored 4–6 weeks after the crisis [14]. If they normalize, the management can be considered complete. If not, it is recommended to search again for TSH receptor autoantibodies-TRAb, even test fT3, administer I-123 or conduct a scan to identify the cause of persistent (>6 weeks) thyrotoxicosis exclude Graves’ disease [13, 14, 52, 54]. In case of Grave’s, antithyroid drugs (methimazole or PTU in the first semester of pregnancy) and beta blocker should be administered—avoid the use of I-131 as it increases the risk of hypothyroidism. If thyrotoxicosis turns into hypothyroidism, levothyroxine should be given at a dose of 1.6 mcg/kg/day orally until TSH reaches normal levels [12, 14, 54]. Another approach of managing a thyrotoxic crisis involves minimal medical interventions, with beta blockers administered only in presence of symptoms and more frequent reassessments of TSH, FT4, i.e., typically every 2–3 weeks [54,55,56,57].

In case of thyroid-like eye disease (TED), high dose systemic corticosteroids are strongly recommended for their potent anti-inflammatory effect. In instances where the orbital thyroidopathy persists, canthotomy/cantholysis may be considered. As for the ICIs treatment, it should only be paused in cases of severe TED [58] (Fig. 1 and Table 4).

Fig. 1
figure 1

Classification of thyroid adverse effects after ICIs therapy

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Table 4 Recommendations for managing ICI-induced thyroid disorders
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Conclusion

The ICI therapy has revolutionized cancer treatment by harnessing the immune system to fight malignancies. While offering promising therapeutic results and improved survival rates for cancer patients, the utilization of ICIs is associated with various adverse effects, among which thyroid disorders are notably prevalent. The pathogenesis of ICI-induced thyroid dysfunction encompasses immune-mediated acute inflammation leading to destructive thyroiditis. T cell activation, alongside the involvement of various antibodies and cytokines, plays a significant role in both initiating and progressing the disease [1, 8, 16, 17].

Diagnosing ICI-related thyroid disorders requires vigilance and regular thyroid function screening, utilizing measurements of TSH, fT4, and TRAb, TPO-antibodies and TSH receptor antibodies, according to specific guidelines [13, 14, 53,54,55,56,57]. Clinical presentations vary from asymptomatic cases to severe manifestations of thyrotoxicosis, hypothyroidism, and even Graves’ disease [24, 30, 32]. Early detection demands a thorough examination encompassing both clinical and laboratory evaluation.

Understanding the pathophysiological mechanisms underlying these adverse effects is vital for the development of effective treatment strategies. The management of these thyroid-related side effects necessitates an individualized approach that considers the severity of the condition, the patient’s clinical state, and the stage of any malignancy involved. As such, a collaborative effort between various medical professionals is essential to ensure optimal care [13, 14, 53, 54, 56]. Guidelines established by prominent organizations such as ASCO, NCCN, SITC, and ESMO serve as a valuable resource for healthcare providers, highlighting the significance of tailored treatments based on the severity grade.

Close monitoring, prompt diagnosis, and personalized treatment strategies are crucial for addressing the complexities of ICI-induced thyroid disorders. Collaboration between healthcare professionals and continuous research are essential for the formulation of future guidelines, the implementation of tailored treatment and the enhancement of ICI therapy.