Isolated Adrenocorticotropin Deficiency due to Nivolumab-induced Hypophysitis in a Patient with Advanced Lung Adenocarcinoma: A Case Report and Literature Review

Ohara, Nobumasa; Ohashi, Kazumasa; Fujisaki, Toshiya; Oda, Chiyumi; Ikeda, Youko; Yoneoka, Yuichiro; Hashimoto, Takehisa; Hasegawa, Go; Suzuki, Kazuo; Takada, Toshinori

doi:10.2169/internalmedicine.9074-17

Cited by 39 publications

(29 citation statements)

References 37 publications

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“…The present case promptly resulted in secondary adrenal insufficiency after transient ACTH elevation. In previous reports, most cases of ICI-induced hypophysitis were diagnosed based on adrenal insufficiency symptoms or hyponatremia with low ACTH and cortisol [5][6][7][8][9][10]. Only one case that resulted in secondary adrenal insufficiency after transient ACTH-dependent Cushing's syndrome was reported [11].…”

Section: Discussionmentioning

confidence: 99%

Nivolumab-induced hypophysitis causing secondary adrenal insufficiency after transient ACTH elevation

et al. 2019

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A 62-year-old man was referred to our department for elevation of plasma ACTH and cortisol levels during nivolumab administration for renal cell carcinoma. Although his ACTH and cortisol levels had been maintained within their reference ranges, they were elevated to 232.7 pg/mL and 21.9 μg/dL, respectively, after eight courses of nivolumab without any subjective symptoms or Cushing's sign. He was hospitalized for endocrinological investigation. ACTH and cortisol returned to their normal ranges (29.18 pg/mL and 11.4 μg/dL, respectively) in the early morning on day 1, but fell down sharply to 3.7 pg/mL and 1.6 μg/dL, respectively, in the early morning on day 2 without subjective symptoms or vital sign changes. Brain magnetic resonance imaging showed no abnormality in his pituitary gland. ACTH response to CRH was apparently normal, but cortisol did not respond to increased ACTH. A rapid ACTH stimulation test showed slightly reduced response of cortisol to exogenous ACTH (1-24). These findings and his clinical course suggested secondary adrenal insufficiency arising from nivolumab-induced hypophysitis. In previous reports, most cases of immune checkpoint inhibitor (ICI)-induced hypophysitis were diagnosed based on adrenal insufficiency symptoms or hyponatremia with low ACTH and cortisol. The ACTH elevation observed in the present case may reflect destruction of the pituitary gland, suggesting that this finding may be important for early detection of ICI-induced hypophysitis. Our case underlines the necessity of close monitoring for subsequent onset of adrenal insufficiency when ACTH elevation is observed during ICI administration.

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Section: Discussionmentioning

confidence: 99%

Nivolumab-induced hypophysitis causing secondary adrenal insufficiency after transient ACTH elevation

et al. 2019

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“…Deficiency of adrenocorticotropic hormone (ACTH) secretion is observed in almost all patients who develop hypopituitarism induced by ICIs [6]. While TSH and/or gonadotropin deficiency is often accompanied by ACTH deficiency in patients treated with anti-CTLA-4 antibodies, almost all patients who develop pituitary dysfunction with anti-PD-1 or anti-PD-L1 antibodies show isolated ACTH deficiency [15]. Central diabetes insipidus is rarely induced by ICIs [6].…”

Section: Overviewmentioning

confidence: 99%

Management of immune-related adverse events in endocrine organs induced by immune checkpoint inhibitors: clinical guidelines of the Japan Endocrine Society

et al. 2019

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Immune checkpoint inhibitors (ICIs) have become a promising treatment for advanced malignancies. However, these drugs can induce immune-related adverse events (irAEs) in several organs, including skin, gastrointestinal tract, liver, muscle, nerve, and endocrine organs. Endocrine irAEs comprise hypopituitarism, primary adrenal insufficiency, thyroid dysfunction, hypoparathyroidism, and type 1 diabetes mellitus. These conditions have the potential to lead to life-threatening consequences, such as adrenal crisis, thyroid storm, severe hypocalcemia, and diabetic ketoacidosis. It is therefore important that both endocrinologists and oncologists understand the clinical features of each endocrine irAE to manage them appropriately. This opinion paper provides the guidelines of the Japan Endocrine Society and in part the Japan Diabetes Society for the management of endocrine irAEs induced by ICIs.

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“…Recently, immune‐checkpoint inhibitor (ICI) has been used for treatment of malignant tumours. As the use of ICI has increased, reported cases of ICI‐induced endocrine dysfunctions such as destructive thyroiditis, hypophysitis and type 1 diabetes have been increased . Anticytotoxic T lymphocyte antigen 4 (CTLA‐4) antibody induces hypophysitis, while cases of antiprogrammed cell death protein 1 (PD‐1) antibody‐induced IAD (PD1‐IAD) were reported .…”

Section: Introductionmentioning

confidence: 99%

“…As the use of ICI has increased, reported cases of ICI‐induced endocrine dysfunctions such as destructive thyroiditis, hypophysitis and type 1 diabetes have been increased . Anticytotoxic T lymphocyte antigen 4 (CTLA‐4) antibody induces hypophysitis, while cases of antiprogrammed cell death protein 1 (PD‐1) antibody‐induced IAD (PD1‐IAD) were reported . Faje et al reported that headaches, pituitary enlargement on MRI and multiple anterior pituitary hormone deficiencies would occur less commonly in anti‐PD‐1 antibody‐induced hypophysitis than in anti‐CTLA‐4 antibody‐induced hypophysitis.…”

Section: Introductionmentioning

confidence: 99%

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Comparative analysis of human leucocyte antigen between idiopathic and anti‐PD‐1 antibody induced isolated adrenocorticotropic hormone deficiency: A pilot study

Inaba

Hiroyuki

Iwakura

et al. 2019

Clinical Endocrinology

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Background: Adult-onset idiopathic isolated adrenocorticotropic hormone deficiency (id-IAD) is a rare disease with unknown aetiology. Recently, numerous cases of anti-PD-1 antibody-induced IAD (PD1-IAD) have been reported, but the clinical course, predictive factors and relationship to id-IAD have not been clarified. Moreover, associations of id-IAD and PD1-IAD with human leucocyte antigen (HLA) require elucidation. Methods: Clinical characteristics of 13 Japanese patients with id-IAD and eightJapanese patients with PD1-IAD were analysed, and HLA-typing test was performed for each patient. Allele and haplotype frequencies of the patients were compared to those of healthy Japanese controls. settings, hyponatremia, disturbance of consciousness and hypoglycaemia were less frequently seen in patients with PD1-IAD than in patients with id-IAD. Conclusions:Distinct clinical characteristics and predisposing HLA allele contributions were proposed between id-IAD and PD1-IAD. Further investigations with greater number of cases are warranted to clarify the detailed mechanisms of id-IAD and PD1-IAD.

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Isolated Adrenocorticotropin Deficiency due to Nivolumab-induced Hypophysitis in a Patient with Advanced Lung Adenocarcinoma: A Case Report and Literature Review

Cited by 39 publications

References 37 publications

Nivolumab-induced hypophysitis causing secondary adrenal insufficiency after transient ACTH elevation

Nivolumab-induced hypophysitis causing secondary adrenal insufficiency after transient ACTH elevation

Management of immune-related adverse events in endocrine organs induced by immune checkpoint inhibitors: clinical guidelines of the Japan Endocrine Society

Comparative analysis of human leucocyte antigen between idiopathic and anti‐PD‐1 antibody induced isolated adrenocorticotropic hormone deficiency: A pilot study

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