(2.12) A Case of Autoimmune Hypothyroidism and New-Onset Diabetes Secondary to Pembrolizumab in a Patient with Metastatic Renal Cell Carcinoma

With advance in cancer immunotherapy, antibodies targeting programmed death 1 receptor (PD-1) such as pembrolizumab have shown promise in multiple malignancies. Despite clinical benefits, anti-PD-1 have been associated with immune related adverse events (irAEs), targeting various organ system. Thyroid dysfunction is the most common endocrinopathy associated with pembrolizumab. However, developing new onset diabetes especially after 1 year is extremely rare.  Patients with new onset diabetes often times present in critical conditions of severe hyperglycemia or diabetic ketoacidosis (DKA). Antibodies for type 1 diabetes (T1DM) were detected in approximately 40% of patients. We describe a patient who developed autoimmune hypothyroidism 2 months after receiving pembrolizumab and a year later new onset diabetes with negative antibodies for T1DM.


Case(s) Description :

A 61-year-old male with a 30-year smoking history and recurrent renal cell carcinoma (RCC) affecting the right kidney with metastasis to the liver 4 years after left nephrectomy for RCC was referred to Endocrinology clinic for evaluation of elevated thyroid stimulating hormone (TSH) level.  Patient was treated with a two-month course of IV pembrolizumab every three weeks.

Patient was complaining of fatigue, constipation, and cold intolerance. Physical examination demonstrated no significant thyromegaly, nodules, or tenderness. TSH was 109 (NL 0.455-4.680 ulU/mL), free T4 was 0.17 (NL 0.78-2.19 ng/dL) and thyroid peroxidase (TPO) antibody was 5559 (NL 0.0-5.5 IU/mL). Patient had normal TSH prior to receiving pembrolizumab. A diagnosis of pembrolizumab-induced hypothyroidism was made. Patient improved after receiving levothyroxine and TSH level became normal. Pembrolizumab had been continued.

One year later, he was admitted with acute confusion, along with polyuria and polydipsia for few weeks. Physical examination was consistent with confusion, tachycardia, BMI of 19.67 kg/m², and looked clinically dehydrated. He was found to have blood glucose (BG) of 642 (NL 65-99 mg/dL), bicarb of 14 (NL 20-32 mmol/L), anion gap of 26 (NL 3-13 mmol/L), venous blood gas showed a pH of 7.29 (NL 7.330-7.430), beta-hydroxybutyrate was 186 (NL 0.20-2.81 mg/dL), and Hemoglobin A1C of 9.0% Patient had normal BG levels prior to this admission. Patient was diagnosed with new onset diabetes complicated by DKA. He was treated with intravenous fluid and regular insulin drip that was transitioned to subcutaneous insulin once DKA resolved.

Further workup revealed negative anti-glutamic acid decarboxylase antibody, negative anti-islet antigen 2, negative anti-islet cell antibody, and negative Zinc Transporter 8 antibody. C-peptide was low at 0.13 (NL 0.80-3.85 ng/mL) with a BG of 617.

Discussion :

Our patient had two endocrine irAEs associated with pembrolizumab treatment, first autoimmune primary hypothyroidism with positive TPO antibody and a year later diabetes with evidence of beta-cell dysfunction while anti-bodies for T1DM were negative. This suggests a multifactorial pathophysiologic mechanism behind the development of endocrinopathies in patients treated with PD-1 inhibitors.