Nivolumab Induced Multiple Endocrinopathies; Adrenal Insufficiency and Primary Hypothyroidism in a Patient With Stage IV Gastric Cancer - A Case Report

Introduction: Nivolumab is a revolutionary immune check point inhibitor (ICI) that changed the world of oncology. It prevents interaction of Program Death Receptor-1 (PD-1) and Program Death Ligand-1 (PD-L1) releasing a cascade of anti-tumor response. However, it has been associated with wide range of autoimmune side effects including gastrointestinal, hepatic, and endocrine side effects. The incidence of nivolumab induced endocrinopathies is relatively rare but increasingly reported. Adrenal insufficiency occurring in <1% of patients, hyperthyroidism in 15.3% and subclinical hypothyroidism in 4.2%. Case Presentations: 81 year old male with stage IV stomach cancer treated with Nivolumab. Prior to immunotherapy initiation, a set of baseline hormones was obtained and was within normal range. 6 months after, routine monitoring showed elevated thyroid stimulating hormone 6.33 mU/L and low FT4 0.59 ng/dL and FT3 0.1 ng/dL. Patient was started on thyroid replacement therapy. After 1 year of Nivolumab therapy, he presented with dizziness and orthostatic hypotension. Laboratory testing was remarkable for low sodium 130 mEq/L, which raised concerns for adrenal insufficiency. Subsequently, ACTH stimulation test showed low cortisol level 15 mcg/dL. Morning cortisol was also low 1.3 mcg/dL. Other pituitary hormones were normal. Patient was started on hydrocortisone with subsequent improvement of symptoms. Discussion: Nivolumab is a human monoclonal antibody that blocks PD-1 and turns off the tumor mediated immune system inhibition. In the meanwhile, ICI also disrupt normal immune signaling mechanisms that lead to decrease immune tolerance and autoimmune diseases. The mechanism of thyroid dysfunction due to ICI remains unclear. PD-1/PD-L1 blockade could induce thyroiditis by diminishing regulatory T cells function. Disruption of interaction between PD-1-expressing lymphocytes and PD-L-expressing thyrocytes –which protects the thyroid gland from autoimmunity– leads to infiltration of the thyroid with autoreactive T and B lymphocytes. Nivolumab induced Adrenal insufficiency is an extremely rare and unclear event, currently, there is no clear evidence that pituitary cells express PD-1. Recently, it was found that the PD-L1 and PD-L2 are expressed in mouse anterior and intermediate pituitary gland, but not the posterior pituitary. This suggests the possibility that specific injury can take place affecting only certain anterior pituitary cells, such as those producing ACTH. Awareness of such endocrinopathies is crucial. Patients should have certain baseline of laboratory data prior to therapy initiation and over the course of treatment. The risk of endocrinopathies is greater at the start of treatment, justifying closer monitoring every visit over the first 6 months, followed by regular monitoring every second visit over the next 6 months and less frequently thereafter.