Isolated adrenocorticotropic hormone deficiency and thyroiditis associated with nivolumab therapy in a patient with advanced lung adenocarcinoma: a case report and review of the literature

Abstract

IntroductionImmune checkpoint inhibitors are a promising class of anticancer drugs. The clinical benefits afforded by immune checkpoint inhibitors can be accompanied by immune-related adverse events that affect multiple organs, and endocrine immune-related adverse events include thyroiditis and hypophysitis. Hypophysitis is less frequent and has a less severe clinical presentation in patients treated with other immune checkpoint inhibitors, such as nivolumab, pembrolizumab, and atezolizumab, than in those treated with ipilimumab. However, studies have described isolated adrenocorticotropic hormone deficiency cases associated with nivolumab, pembrolizumab, and atezolizumab therapy, most of which occurred during the course of immune checkpoint inhibitor therapy. We report a rare case of patient with isolated adrenocorticotropic hormone deficiency that occurred after nivolumab therapy.Case presentationA 69-year-old Japanese woman with advanced lung adenocarcinoma developed painless thyroiditis with transient elevations of serum thyroid hormones during 3 months of cancer treatment with nivolumab and began thyroid hormone replacement therapy for subsequent primary hypothyroidism. Four months after nivolumab therapy was discontinued, she developed isolated adrenocorticotropic hormone deficiency; corticosteroid replacement therapy relieved her secondary adrenal insufficiency symptoms, such as anorexia and fatigue. Human leukocyte antigen typing revealed the presence of DRB1*04:05-DQB1*04:01-DQA1*03:03 and DRB1*09:01-DQB1*03:03-DQA1*03:02 haplotypes, which increase susceptibility to autoimmune polyendocrine syndrome associated with thyroid and pituitary disorders in the Japanese population.ConclusionsOur patient developed thyroiditis during cancer treatment with nivolumab and subsequently exhibited isolated adrenocorticotropic hormone deficiency 4 months after discontinuing the drug. Administration of nivolumab in combination with a genetic predisposition to polyglandular autoimmunity probably caused both the thyroiditis and hypophysitis, resulting in primary hypothyroidism and isolated adrenocorticotropic hormone deficiency, respectively, in our patient. The present case highlights the need for physicians to be aware that endocrine immune-related adverse events, including hypophysitis, can occur more than several months after discontinuing a drug.

Anti-PD1 and Anti-PDL1-Induced Hypophysitis: A Cohort Study of 17 Patients with Longitudinal Follow-Up

“…After this one-year period, laboratory evaluation is recommended in case of clinical signs [ 30 ], but we believe that clinicians should remain vigilant after this period because such signs may be difficult to detect. Furthermore, there is no recommendation regarding follow-up after discontinuation of ICI although some cases have occurred after the discontinuation [ 10 , 12 , 15 ].…”

“…The descriptions of PD1 and PDL1 inhibitor-induced hypophysitis are more recent, probably because these drugs have been approved more recently than the approval of CTLA4 inhibitor. Some case reports described isolated adrenocorticotropic hormone (ACTH) deficiency associated with PD1 and PDL1 inhibitors [ 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ].…”

Diagnosis and management of toxicities of immune checkpoint inhibitors in hepatocellular carcinoma

“…Importantly, this irAE can occur several months after discontinuing an ICI. 78 Hypopituitarism and adrenal disorders associated with chronic liver disease The dysfunction of the hypothalamic-pituitaryadrenal axis in patients with liver disease has been extensively described and worsens in parallel with the severity of cirrhosis. 79 Relative adrenal insufficiency is well described 80 but mainly in decompensated cirrhotics who are not candidates for immunotherapy.…”

Nivolumab-induced hypothyroidism followed by isolated ACTH deficiency

“…When hypophysitis occurs, the order of hormone deficiency in anterior pituitary is usually ACTH deficit, followed by TSH, luteinising hormone/follicle-stimulating hormone and later growth hormone 13. In most cases that described of nivolumab-induced hypophysitis, isolated ACTH was reported 11 14–17. To our knowledge, to date, there have been two case reports where impairment of the adrenocortical and gonadal axes was described following nivolumab-induced hypophysitis; in both cases, there was also primary thyroid dysfunction secondary to nivolumab treatment 18 19.…”

“…The thyrotoxic phase was asymptomatic and rapidly evolved into overt hypothyroidism, reinforcing the need to routinely evaluate thyroid function in these patients. Although extremely rare, ACTH deficiency following nivolumab treatment has been reported and can occur at any time of treatment, even after the drug was suspended 16 17. As ACTH deficiency usually develops insidiously in this setting, clinical suspicion is crucial in order to avoid adrenal crisis.…”