**4. Thyroid Dysfunction**

Among endocrinopathies occurring as irAEs, thyroid dysfunction is the most frequent. Although thyroid dysfunction is mainly caused by thyrotoxicosis, while hypothyroidism is caused by destructive thyroiditis, the occurrence of Basedow's disease after the administration of anti CTLA-4 antibodies has also been reported [33,34]. The reported incidence of thyroid dysfunction with the use of anti-PD-1 antibodies is 5–10%. The incidence of thyroid dysfunction is higher with the use of anti-PD-L1 antibodies (0–5%) and anti-CTLA-4 antibodies (0–5%) [19–21]. In a previous systematic review and meta-analysis, increased use of combination treatment was observed, with hypothyroidism occurring in 16.4% cases treated with nivolumab combined with ipilimumab [12]. Moreover, the incidence of hypothyroidism was significantly higher with ICI treatment than with chemotherapy and placebo treatment [12]. In other studies, thyroid dysfunction was more frequent in cases treated with anti-thyroglobulin (Tg) antibody (anti-TgAb) and anti-thyroid peroxidase antibody (anti-TPOAb) than in cases treated without these antibodies before nivolumab treatment initiation; this finding may be beneficial for predicting the onset of thyroid dysfunction [35,36]. Destructive thyroiditis occurs within a few weeks after ICI treatment initiation in many cases, and it may present with thyrotoxicosis [37–39]. Subsequently, patients may exhibit a transition to hypothyroidism within 3–6 weeks [37–40]. In a previous study, 12 of 99 patients who received pembrolizumab developed thyrotoxicosis, and transition to hypothyroidism occurred in nine of the 12 patients [39]. Another study found thyrotoxicosis in six of 10 patients who developed indolent thyroiditis after pembrolizumab treatment initiation; all six patients exhibited a transition to hypothyroidism after four weeks [38].

Symptoms of thyrotoxicosis include palpitations, sweating, fever, diarrhea, tremors, weight loss, and general fatigue. Neck pain is generally not observed. Blood tests show a decreased serum TSH level, elevated serum free T3 (FT3) and free T4 (FT4) levels, and negativity for thyroid receptor antibody (TRAb). Quite often, anti-TgAb and anti-TPOAb are positive [30,36]. In addition, there are many cases in which the increased serum Tg level is recognized by destruction of the thyroid gland, and it is said that the Tg level normalizes upon transitioning to hypothyroidism [40]. Thyroid echography frequently shows decreased blood flow and an internal heterogeneous low signal intensity. FDG-PET also shows increased uptake, while thyroid scintigraphy shows decreased iodine uptake [38].

Hypothyroidism may develop after thyrotoxicosis or simultaneously with the onset of thyroiditis. If the latter occurs, positivity for anti-TgAb and anti-TPOAb is seen in several cases [37]. Major symptoms include general fatigue, loss of appetite, constipation, bradycardia, and weight gain. Blood tests show elevated serum TSH and decreased serum FT4 and FT3 levels. In mild cases, a slightly high TSH level may result in a state of occult hypothyroidism. Thyroid echography may show decreased blood flow, parenchymal hypointensity, and atrophy. Hypothyroidism secondary to hypopituitarism must be ruled out in patients showing hypothyroidism. Hypopituitarism can be suspected when serum FT4 levels are low and TSH levels are low to normal. Differentiation should be cautious because low serum FT3 levels also occur in the end stages of malignancy and in low T3 syndrome complicating

severe infections. In low T3 syndrome, the serum FT3 level is low and the serum FT4 level is normal or slightly decreased, while the serum TSH level is normal.

The mechanism by which ICIs cause thyroid dysfunction has not been clarified, but it has been suggested that the expression of PD-L1 and programmed death ligand 2 in the thyroid tissue plays a role [41].
