Late Manifestation of Hypothyroidism Due to Thyroiditis with Elevated Auto-Antibody Titers in a Patient on Immune Checkpoint Inhibitor Therapy

Immune checkpoint inhibitors (ICPi) are cornerstones in cancer therapy. They block checkpoint proteins including Cytotoxic T Lymphocyte Antigen-4(CTLA-4), Programmed Death-1 (PD-1) and their ligands like PD-Ligand- 1(PDL1), thus activating various immune pathways, increasing tumor susceptibility to surveillance and destruction. They also decrease self-tolerance, causing immune related adverse effects (irAE), including endocrinopathies. We report a case of primary hypothyroidism induced by immunotherapy, detected months after its initiation. 

Case Description :

A 79 year old female with high grade stage IV small cell carcinoma of the lung(TxN3M1c) with metastases to the neck, mediastinum, abdomen and spine and no prior thyroid disease, received treatment with the anti-PDL1 agent, Atezolizumab. Six months later, she presented with altered mental status. History was negative for traumatic, vascular, infectious or metabolic etiologies.

Examination revealed lack of orientation but no focal neurologic deficits. Systemic and thyroid examinations were normal.

Work up revealed hyponatremia (Na 127meq/L) and TSH elevation to 24.4 mIU/L with level prior to ICPi use of 1.2 mIU/L. Thyroid function tests revealed TT4 of 3.3mcg/dl(5-12.2), FT4 of 0.61ng/dl(0.8-1.5) and FT3 of 1.64pg/ml(2.5-3.9). Anti Thyroid Peroxidase(TPO) and Anti Thyroglobulin(TG) antibody levels were elevated to 7516.5IU/ml(0-5.6) and 49.7U/ml(0-4.1) respectively. Myxedema score was low at 20. Ultrasound imaging showed a diffusely heterogeneous thyroid gland. 

Cranial imaging revealed extensive cerebral metastases with normal appearing pituitary gland. This was deemed the cause of encephalopathy. She received steroids and radiation to the whole brain, leading to improvement.

Grade 2 thyroiditis was diagnosed and 50mcg daily (1.3mcg/kg) of Levothyroxine(LT4) started while immunotherapy was continued. TSH level then fell to 11.3 mIU/L and she was discharged on LT4 50mcg daily.

Although necessary to exclude coexistent adrenal insufficiency in this setting, the patient had been receiving exogenous corticosteroids, precluding measurement of ACTH or Cortisol levels.

Discussion :

Thyroid dysfunction is a common endocrinopathy caused by ICPi. The incidence of hypothyroidism is double that of thyrotoxicosis(6.6 vs 2.9%). The median time to detection ranges from 4 to 8 weeks post immunotherapy with that to hypothyroidism being longer than that to thyrotoxicosis (63 vs 21 days), indicating that the latter may be an initial transient phase. In our case, hypothyroidism was detected 6 months after ICPi use.

The mechanism of dysfunction is destructive immune thyroiditis. The role of autoantibodies including anti TPO or anti TG antibodies is unclear. It is also unknown whether those with high antibody titers at baseline have an increased risk of developing ICPi induced thyroiditis.

Therapy with Levothyroxine may be started at a lower than conventional dose of 0.8mcg/kg and modified as needed. Immunotherapy must be modified based on the grade of dysfunction.
The occurrence of endocrine irAE has been associated with better outcomes and improved overall survival in patients.