Multiple endocrinopathies, hypercalcaemia and pancreatitis following combined immune checkpoint inhibitor use- case report and review of literature

Abstract

Background Immune checkpoint inhibitors (ICIs) are a novel class of oncological agents which are used to treat a number of malignancies. To date seven agents have been approved by the Food and Drug Administration (FDA) to treat both solid and haematological malignancies. Despite their efficacy they have been associated with a number of endocrinopathies. We report a unique case of hypophysitis, thyroiditis, severe hypercalcaemia and pancreatitis following combined ICI therapy. Case presentation A 46-year old Caucasian female with a background history of malignant melanoma and lung metastases presented to the emergency department with lethargy, nausea, palpitations and tremors. She had been started on a combination of nivolumab and ipilimumab 24 weeks earlier. Initial investigations revealed thyrotoxicosis with a thyroid stimulating hormone (TSH) of < 0.01 (0.38–5.33) mIU/L, free T4 of 66.9 (7–16) pmol/.L. TSH receptor and thyroperoxidase antibodies were negative. She was diagnosed with thyroiditis and treated with a beta blocker. Six weeks later she represented with polyuria and polydipsia. A corrected calcium of 3.54 (2.2–2.5) mmol/l and parathyroid hormone (PTH) of 9 (10–65) pg/ml confirmed a diagnosis of non-PTH mediated hypercalcaemia. PTH-related peptide and 1, 25-dihydroxycholecalciferol levels were within the normal range. Cross-sectional imaging and a bone scan out ruled bone metastases but did reveal an incidental finding of acute pancreatitis – both glucose and amylase levels were normal. The patient was treated with intravenous hydration and zoledronic acid. Assessment of the hypothalamic-pituitary-adrenal (HPA) axis uncovered adrenocorticotrophic hormone (ACTH) deficiency with a morning cortisol of 17 nmol/L. A pituitary Magnetic Resonance Image (MRI) was unremarkable. Given her excellent response to ICI therapy she remained on ipilimumab and nivolumab. On follow-up this patient’s thyrotoxicosis had resolved without anti-thyroid mediations – consistent with a diagnosis of thyroiditis secondary to nivolumab use. Calcium levels normalised rapidly and remained normal. ACTH deficiency persisted, and she is maintained on oral prednisolone. Conclusion This is a remarkable case in which ACTH deficiency due to hypophysitis; thyroiditis; hypercalcaemia and pancreatitis developed in the same patient on ipilimumab and nivolumab combination therapy. We postulate that hypercalcaemia in this case was secondary to a combination of hyperthyroidism and secondary adrenal insufficiency.

Adrenal Insufficiency and Thyrotoxicosis Following Combined Immune Checkpoint Inhibitor Use: A Case Report and Literature Review

“…Although there have been several reports of multiple endocrine irAEs caused by ICI combination therapy, only four cases of AI and thyrotoxicosis due to nivolumab and ipilimumab therapy have been reported (Table 4) [21][22][23][24]. Previous reports indicate that the duration before the onset of hypophysitis and thyrotoxicosis caused by a combination of anti-PD-1 and anti-CTLA-4 antibodies differs, averaging 10.3 weeks and two weeks after the first administration, respectively [4][5][6].…”

Immune checkpoint inhibitors and acute kidney injury

“…The causes of electrolyte abnormalities are diverse. Immune-endocrine disease is an important cause of electrolyte abnormalities, such as hypophysitis, adrenal insufficiency, primary hyperparathyroidism and hypothyroidism (144)(145)(146). In the study by Patel et al, the mechanisms of hyponatremia include hypovolemic hyponatremia due to hemodynamic disorders caused by volume depletion, hypervolemic hyponatremia due to CHF or nephrosis, syndrome of inappropriate antidiuretic hormone secretion, and endocrine diseases (147).…”

Management of adrenal insufficiency

“…Furthermore, the increasing use of drugs such as immune checkpoint inhibitors and the endocrinopathy side effects associated with these further supports the need for all physicians, not just endocrinologists, to recognize, and promptly initiate treatment AI. [9,10] In the current issue of the Journal of Diabetes and Endocrine Practice, Beshyah and Ali have clearly highlighted the need for urgent clinician education on the management of patients with AI within multiple disciplines including endocrinology, in the Middle Eastern/Northern African (MENA) countries. [11] options for gluCoCortiCoid rEplaCEmEnt Glucocorticoid replacement therapy is the cornerstone of AI management.…”

“…Furthermore, the increasing use of drugs such as immune checkpoint inhibitors and the endocrinopathy side effects associated with these further supports the need for all physicians, not just endocrinologists, to recognize, and promptly initiate treatment AI. [9,10]…”