Endocrine Abstracts

Case history: At 1 year follow-up post excision of invasive melanoma, a 63-year-old gentleman, with no other significant past medical history, was found to have CT evidence of metastatic disease. In the absence of a BRAF mutation, he was consented for combination immunotherapy with Ipilimumab (anti-CTLA4) and Nivolumab (anti-PD1). Monitoring bloods during cycle 2 of treatment revealed asymptomatic thyroiditis (TSH 0.03 miu/l, T4 35.5 pmol/l, T3 15.1 pmol/l), which did not require medication. However during cycle 3, the patient was admitted with polydipsia, polyuria and weight loss. Investigations revealed glucose 30.4 mmol/l, ketones 0.6 mmol/l, HbA1c 9.4% and weakly positive anti-GAD antibodies. He was diagnosed with new-onset type 1 diabetes and commenced on basal bolus insulin. Three days later, blood tests demonstrated development of primary hypothyroidism (TSH 10.51 miu/l, FT4 <5.2 pmol/l, FT3 <1.5 pmol/l, cortisol 641 nmol/l), hence levothyroxine therapy was commenced. Glycaemic control worsened however, with unexplained hypoglycaemia despite reduction in basal insulin. He was admitted one week later with fatigue, postural hypotension and collapse. He denied any headache or visual disturbances.

Investigations: Notwithstanding acute illness, cortisol was inappropriately low (44 mmol/l) with concurrent hyponatraemia (Na 122 mmol/l). Adrenal insufficiency was confirmed with a short synacthen test, which demonstrated an inadequate rise in cortisol from 35 mmol/l to 300 mmol/l. Pituitary profile showed TSH 21.09 miu/l, FT4 5.8 pmol/l, prolactin 106 mu/l, FSH 3.0 iu/l and LH 0.9 iu/l. MRI brain showed no radiological evidence of hypophysitis.

Management: Emergency treatment of acute adrenal insufficiency was commenced with 100 mg hydrocortisone IV followed by 50 mg hydrocortisone IV every 6 hours, and intravenous rehydration as per society guidelines. Recovery was rapid, and he was changed to oral hydrocortisone. Previously erratic glycaemic control improved considerably, with resolution of hypoglycaemia.

Discussion: Endocrine complications of checkpoint inhibitor therapy are well recognized, with adrenal insufficiency reported in 2.6% of patients, primary hypothyroidism in 15.0% (particularly associated with Nivolumab treatment) and type 1 diabetes in 0.4%. Hypophysitis causing ACTH and TSH deficiency is reported in up to 7.7% of cases, and is often unassociated with clinical or radiological features of mass effect. Our patient experienced transient hyperthyroidism, then type 1 diabetes, subsequent primary hypothyroidism and finally adrenal insufficiency. The index of suspicion for concomitant endocrinopathies should be particularly high with checkpoint inhibitors, which are increasingly indicated for various malignancies. Biochemical monitoring protocols are crucial as clinical symptoms may occur late. Close collaboration between oncology and endocrinology teams is therefore essential when following up such patients, to facilitate early recognition and management of these complications.