With the widespread use of immunosuppressants in patients with PLC, we should not only pay attention to the curative effect, but also attach importance to the adverse reactions. TD is one of the common immune related adverse reactions caused by immunosuppressants. In this retrospective study, we found that more than half of PLC patients had TD after treatment of PD1, most of them showed hypothyroidism, mainly primary, subclinical and severity grade 1–2. The degree of liver cirrhosis and treatment methods may have an impact on TD. The vast majority of TD patients have a good prognosis.
At present, the reports of TD caused by immunosuppressant PD-1 monoclonal antibody treatment mostly come from clinical trials, rather than real-world studies, especially less studies of PD-1 monoclonal antibody treatment of PLC. As a real-world retrospective study, through the analysis of the clinical data of PLC patients after PD-1 treatment, we found that the incidence of thyroid adverse reactions can be as high as 57.9%, higher than 3.4% − 47.7% [2, 7], reported in previous Meta analysis of drug clinical trials, 42.37% reported by Wei Fenfen [8] and 29.0% reported by Yang Zizhong [9]. There were two main reasons for this difference. On the one hand, previous studies mostly involved lung cancer, melanoma, gastrointestinal tumors, breast cancer, hematological system tumors, etc, while PLC patients were rarely included in the above studies. PLC patients often had hepatitis B (C) virus infection and liver cirrhosis, accompanied by worse thyroid function. In our study, 80% of PLC patients were in Barcelona phase C and complicated with hepatitis B (C) virus infection and cirrhosis. On the other hand, less than 20% of PLC patients in our study have previously undergone surgical resection, and more than half of them have received TAE / TACE, tumor ablation and targeted drug therapy, which will promote the production of TD [10, 11] .In addition, the selection of therapeutic drugs may also affect the incidence of TD. There had few reports on the use of cindilimab and carrelizumab in previous studies, although there was no significant difference between the two antibodies in the incidence, type and severity of TD. At present, the pathogenesis of TD in PLC patients caused by PD-1 treatment is not clear, which may be related to patients' basic thyroid diseases, basic level of thyroid stimulating hormone and thyroid antibody, changes in the number and function of immune cells, tumor microenvironment, homology of antigen expressed between tumor and thyroid tissue, body mass index, etc [12, 13]. It is speculated that it may be the direct effect of drugs on thyroid function or the result secondary to thyroiditis.
We found that the incidence of hypothyroidism and hyperthyroidism were 47.7% and 10.3% respectively in PLC patients treated with PD-1, hypothyroidism was 4.6 times higher than hyperthyroidism. Previous meta-analysis had reported that the incidence of hypothyroidism after PD-1 treatment was 10% − 16.4%, and the incidence of hyperthyroidism was 9%-10.4%. There was little difference between the two, but our study showed that the incidence of hypothyroidism was much higher than that of hyperthyroidism. Previous meta-analysis [14] reported that the incidence of hypothyroidism after PD-1 treatment was 10% − 16.4%, and the incidence of hyperthyroidism was 9% − 10.4%. There was little difference between the two, but our study showed that the incidence of hypothyroidism was much higher than that of hyperthyroidism. The incidence of hypothyroidism in these patients is high, but not serious. Less than 1 / 3 of them have clinical symptoms, and only 7.5% of them have adverse reactions above grade 3. On the contrary, the incidence of hyperthyroidism in these patients is low, but more than 2 / 3 of them have clinical symptoms, and 15.0% of them have adverse reactions above grade 3. Among the 10 patients with severity above grade 3, there were 3 patients with hyperthyroidism and 7 patients with hypothyroidism. Except that 2 patients with hyperthyroidism did not fully recover and 2 patients with hypothyroidism died of liver failure, the remaining 1 patient with hyperthyroidism and 5 patients with hypothyroidism fully recovered after treatment. Therefore, as long as TD can be found in time and treated actively, most patients with TD have a good prognosis. The high incidence of subclinical TD suggests that we need to closely monitor thyroid function in the process of PD-1 treatment of PLC. When patients have common clinical symptoms of TD, such as fatigue, palpitation, loss of appetite, weight loss, edema and irritability, we need to be vigilant and give diagnosis and treatment in time to reduce the possibility of interrupting PD-1 treatment.
We also found some interesting differences. For example, the proportion of decompensated liver cirrhosis was higher in the hypothyroidism group, especially in the clinical hypothyroidism group and the primary TD group, and the proportion of patients with previous surgery was higher in the hyperthyroidism group, especially in the clinical hyperthyroidism group, and the proportion of patients with previous or combined use of targeted drugs was the highest in the primary TD group. Previous studies have found that the liver is an organ that has an important impact on thyroid hormone metabolism in addition to the thyroid [15, 16]. The transformation and inactivation of thyroid hormones require the participation of the liver, including metabolic processes such as deiodination, deamination and combined bile secretion, and the synthesis of thyroid hormone binding protein is also completed in the liver. If the damage of hepatocytes leads to the decline of liver function, the production of thyroid hormone and binding protein will be significantly affected, resulting in the decrease of thyroid hormone and even thyroid atrophy and degradation, especially in decompensated liver cirrhosis. Therefore, it is easier to develop hypothyroidism in patients with decompensated liver cirrhosis who use immunosuppressants such as PD-1 to produce TD. The reason why the proportion of patients with hyperthyroidism treated by surgical resection increased significantly may be related to the high probability of surgical resection caused by the early detection of PLC. Due to the high recurrence rate of liver cancer after operation, the total diagnosis and treatment time of these patients is longer because of the subsequent recurrence and treatment. Therefore, trauma and stress caused by surgical treatment itself, immune function damage, and the ability to receive more iodine containing contrast agents in the process of long-term diagnosis and treatment may be part of the inducement for hyperthyroidism after PD-1 treatment [17]. PD-1 combined with molecular targeted drugs was commonly used in the treatment of liver cancer. The targeted drugs were tyrosine kinase inhibitors (TKIs), including sorafenib, renvatinib, bevacizumab and regofinib. Previous studies had shown that the probability of TD after TKIs treatment was high. Koizumi et al [18] found that there were 7 (14.0%), 26 (52.0%) and 5 (10.0%) patients with subclinical hypothyroidism, dominant hypothyroidism and thyrotoxicosis in 50 patients with advanced liver cancer treated with renvatinib. At present, it was considered that the mechanism of TD caused by TKIs drugs may be related to the effect of drugs on tyrosine kinase in thyroid vascular function. For example, TKIs inhibits blood vessels, leading to ischemic thyroiditis, causing transient thyrotoxicosis, or hypothyroidism due to the decrease of thyroid blood supply and the gradual destruction of thyroid gland [19, 20]. In addition, TKI could also affect the synthesis of thyroid hormone by inhibiting the transport of iodothyronine [21] and produce immunostimulatory properties by inhibiting the expression of CTLA4 and PD1 on CD4 + T and CD8 + T cells [22]. Therefore, PD-1 inhibitors combined with targeted drugs were more prone to primary TD in the treatment of liver cancer.