SAT-514 Nivolumab Related Primary Hypothyroidism: 3 Years of Follow-Up

BACKGROUND: Primary hypothyroidism is one of the most common endocrinopathies related to the use of nivolumab, a monoclonal antibody against the immune checkpoint molecule programmed death-1 (PD-1). The long-term course of this condition, especially after the completion of nivolumab treatment, has not been widely reported. CLINICAL CASE: A 70-year-old man presented with weight gain despite poor appetite, cold intolerance, and constipation. He noticed these symptoms after receiving the first three months of treatment with nivolumab for renal cell carcinoma. His heart rate was 66, blood pressure was 130/79 mm Hg, and body mass index was 28.3. The thyroid gland was normal-sized without palpable nodules, deep tendon reflexes were normal, and cardiac and pulmonary exams were unremarkable. Laboratory test results were consistent with primary hypothyroidism: thyroid-stimulating hormone (TSH) was elevated at 97.11 mIU/L (normal, 0.35-4.70 mIU/L), and total thyroxine was less than 1 mcg/dL (normal, 4.5-12.0 mcg/dL). Both anti-TPO antibody (222.6 IU/ml, normal<5.6 IU/ml) and anti-thyroglobulin antibody (10.6 IU/ml, normal <4.1 IU/ml) levels were elevated. There was no prior history of thyroid disease; two of the patient’s sisters had chronic hypothyroidism. Treatment with levothyroxine resulted in rapid resolution of symptoms. With dose titration of levothyroxine over the course of a few months, the patient achieved biochemical euthyroidism. Nivolumab therapy was continued for more than two years, during which a stable levothyroxine dose was maintained, and the patient remained clinically and biochemically euthyroid. Ultimately the renal cell carcinoma was determined to be in remission, and nivolumab therapy was stopped. Subsequently, the anti-TPO antibody titer was observed to have returned to the normal range (2.3 IU/ml). However, as of five months following discontinuation of nivolumab, and 32 months since the onset of thyroid dysfunction, the patient’s hypothyroidism persists as reflected by non-suppressed TSH values on levothyroxine treatment. CONCLUSION: We have observed the course of nivolumab-induced primary hypothyroidism over almost three years in an individual patient. The hypothyroidism has persisted, requiring ongoing levothyroxine replacement at a dose of approximately 1.4 mcg/kg daily. An interesting feature of this case is the disappearance of anti-TPO antibody positivity after discontinuation of nivolumab. We speculate that the ongoing hypothyroidism despite the absence of detectable autoantibodies may be related to progressive thyroid cell apoptosis. Further long-term observations will determine whether permanence of nivolumab-induced hypothyroidism is the rule.