Management of Thyrotoxicosis Induced by PD1 or PD-L1 Blockade

Alessandro Brancatella; Isabella Lupi; Lucia Montanelli; Debora Ricci; Nicola Viola; Daniele Sgrò; Lucia Antonangeli; Chiara Sardella; Sandra Brogioni; Paolo Piaggi; Eleonora Molinaro; Francesca Bianchi; Michele Aragona; Andrea Antonuzzo; Andrea Sbrana; Maurizio Lucchesi; Antonio Chella; Alfredo Falcone; Stefano del Prato; Rossella Elisei; Claudio Marcocci; Patrizio Caturegli; Ferruccio Santini; Francesco Latrofa


J Endo Soc. 2021;5(9) 

In This Article

Abstract and Introduction


Context: Thyrotoxicosis is a common immune-related adverse event in patients treated with programmed cell death protein-1 (PD1) or programmed cell death protein ligand-1 (PD-L1) blockade. A detailed endocrinological assessment, including thyroid ultrasound and scintigraphy, is lacking, as are data on response to treatment and follow-up.

Objective: The aim of this study was to better characterize the thyrotoxicosis secondary to immune checkpoint inhibitors, gaining insights into pathogenesis and treatment.

Methods: We conducted a retrospective study of 20 consecutive patients who had normal thyroid function before starting immunotherapy and then experienced thyrotoxicosis on PD1 or PD-L1 blockade. Clinical assessment was combined with thyroid ultrasound, 99mtechnecium scintiscan, and longitudinal thyroid function tests.

Results: Five patients had normal or increased scintigraphic uptake (Sci+), no serum antibodies against the thyrotropin receptor, and remained hyperthyroid throughout follow-up. The other 15 patients had no scintigraphic uptake (Sci–) and experienced destructive thyrotoxicosis followed by hypothyroidism (N = 9) or euthyroidism (N = 6). Hypothyroidism was more readily seen in those with normal thyroid volume than in those with goiter (P = .04). Among Sci– individuals, a larger thyroid volume was associated with a longer time to remission (P < .05). Methimazole (MMI) was effective only in Sci+ individuals (P < .05).

Conclusion: Administration of PD1- or PD-L1–blocking antibodies may induce 2 different forms of thyrotoxicosis that appear similar in clinical severity at onset: a type 1 characterized by persistent hyperthyroidism that requires treatment with MMI, and a type 2, characterized by destructive and transient thyrotoxicosis that evolves to hypothyroidism or euthyroidism. Thyroid scintigraphy and ultrasound help in differentiating and managing these 2 forms of iatrogenic thyrotoxicosis.


Immune checkpoint inhibitors (ICIs) are monoclonal antibodies directed toward receptors expressed on T cells and other cell types of peripheral tissue, namely cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed cell death protein-1 (PD1), and programmed cell death protein ligand-1 (PD-L1). By blocking these molecules, ICIs promote the activation of the immune system against cancer and as such are effective in the treatment of many solid tumors.[1,2] The hyperactivation of the immune system induced by ICIs can also generate a broad spectrum of inflammatory tissue reaction acknowledged as immune-related adverse events (irAEs).[2] Thyroid dysfunction and hypophysitis are the most common endocrine irAEs, followed by type 1 diabetes and adrenalitis, whereas autoimmune hypoparathyroidism and central diabetes insipidus have been less frequently reported.[3–5] Thyroid dysfunction can be a consequence of PD1 and PD-L1 blockade; however, it has not been fully characterized because trials have focused for the most part on the epidemiology of irAEs rather than on their clinical presentation and course.

An exhaustive endocrinological investigation, including a systematic analysis of thyroid ultrasound and scintigraphy, as well as data on the response to treatment and follow-up, are lacking.

The aim of the present study was to characterize ICI-induced thyrotoxicosis by hormonal and antibodies assessment and thyroid ultrasound and scintigraphic imaging in order to gain insights into its pathogenesis and to guide its management.