Type 1 Diabetes, ACTH Deficiency, and Hypothyroidism Simultaneously Induced by Nivolumab Therapy in a Patient with Gastric Cancer: A Case Report

Immune checkpoint inhibitors (ICIs), targeting programmed cell death protein 1 (PD-1) or its ligand (PD-L1), and cytotoxic T-lymphocyte antigen 4 (CTLA-4) have broadened options and improved efficacy in treating various cancers. Nivolumab, a human immunoglobulin G4 monoclonal antibody, binds to the PD-1 receptor interfering with the binding of PD-L1 and PD-L2, which results in decreasing the immune-suppressive signal from the T cells [1]. ICIs are reported to induce unique immune-related adverse events (irAEs) because of dysregulation of immune activation [2, 3]. Different irAE profiles based on type of ICIs are known, and pneumonitis, hypothyroidism, arthralgia, and vitiligo have been reported to be frequent irAEs with anti-PD-1 antibodies [4]. Endocrinopathies, such as thyroid dysfunction, adrenal insufficiency, hypophysitis, and type 1 diabetes mellitus, are also associated with ICIs, but the incidence of endocrinopathies other than thyroid dysfunction is very low [5]. This report highlights nivolumab-induced multi-endocrinopathies in which type 1 diabetes, adrenocorticotropic hormone (ACTH) deficiency, and hypothyroidism simultaneously occurred in a patient with gastric cancer.

A 70-year-old male with a medical history of hypertension was diagnosed with T3, N1, M0, stage IIB gastric cancer (Japanese Classification of Gastric Carcinoma, the 14th Edition) that was treated by distal gastrectomy in June 2012. In August 2016, the patient had a remnant gastrectomy due to T1b, N0, M0, stage IA esophagogastric junction cancer. He was also diagnosed with upper esophagus cancer. An endoscopic submucosal dissection was performed, and subsequent postoperative adjuvant chemotherapy (fluorouracil, cisplatin) was administered for the positive margin. In April 2018, 2nd-line chemotherapy (ramucirumab, paclitaxel) was conducted, due to an elevation in a tumor marker which led to a suspected relapse.

In November 2018, nivolumab was initiated because peritoneal dissemination was suggested by computed tomography. At that time, diabetes mellitus was not noted by investigations for which hemoglobin A1c (HbA1c) and casual blood glucose were 6.3% and 154 mg/dL, respectively. Eight months later, he was referred to our department due to blood sugar elevation (HbA1c 9.4%, casual blood glucose 219 mg/dL, C-peptide <0.03 ng/mL), for which insulin therapy was prescribed with a diagnosis of type 1 diabetes induced by nivolumab. At the time, free T4 and thyroid-stimulating hormone (TSH) levels were noted as normal. A month after the introduction of insulin, the patient was transferred to our hospital due to hypoglycemia and disturbance of consciousness. He required emergency hospitalization due to persistent impaired consciousness that was observed after the dextrose administration.

A physical examination revealed that he had an impaired consciousness of E4V4M5 according to the Glasgow Coma Scale. His blood pressure was 153/80 mm Hg, his pulse was 100 per minute, he was respirating at a rate of 20 breaths per minute, and his temperature was 36.4°C. Other examinations, including the head and neck, chest, abdomen, and neurology, were otherwise normal.

A complete blood count and basic biochemical test produced an almost normal result, except for a slight anemia (Hb 10.8 g/dL) and hyponatremia (130 mmol/L) (Table 1). The patient experienced a prolonged fever and an impaired consciousness after admission and presented with frequent episodes of hypoglycemia. For these reasons, a further assessment of his hormones was conducted. The results of the hormone test were a low ACTH (3.4 pg/mL), cortisol (1.39 μg/dL), free T4 (0.66 ng/dL), and elevated TSH level (10.698 μIU/mL) (Table 2). Imaging showed a slight enlargement of the thyroid gland by ultrasound and an otherwise normal pituitary gland with partial empty sella, as well as deviated pituitary stalk by magnetic resonance imaging.

We diagnosed him with nivolumab-induced type 1 diabetes, ACTH deficiency, and hypothyroidism. The ACTH deficiency was treated with steroid replacement after 12 days in hospital (hydrocortisone 10 mg/day). Hypothyroidism was treated with thyroid hormone treatment (levothyroxine 25 μg/day) 2 weeks after the steroid was initiated. Dose adjustment of insulin was done during steroid and thyroid hormone replacement therapy. Soon after the treatment, he became afebrile, alert, and a reduced number of hypoglycemic episodes was noted (Fig. 1). His activities of daily living (ADL) level was low, at bed rest, on the day of admission, but he regained a satisfactory level in ADL soon after the initiation of therapy. He was discharged on day 35 due to good progress, after adjusting the doses of hydrocortisone and insulin. In January 2020, he received a followed-up in an outpatient setting, with insulin, hydrocortisone, and thyroid replacement therapy and no relapses without nivolumab treatment.

There are 2 important clinical issues evident from our case. Multiple endocrinopathies induced by nivolumab can possibly occur at the same time, despite low frequency of adverse events in each endocrine organ. Further hormone investigations are necessary when regular treatment intervention is not effective or unexplained symptoms are observed.

Firstly, multiple endocrinopathies induced by nivolumab can occur simultaneously. In a clinical trial of nivolumab administered to gastric cancer patients, a type of thyroid gland deficiency was reported in 4% of cases for which hyperthyroidism and hypothyroidism were seen in 0.6 and 3%, respectively. Type 1 diabetes and hypopituitarism/hypophysitis are rarer conditions, which were reported in 0.9 and 0.3%, respectively [6-8]. There are some previous reports of type 1 diabetes with isolated ACTH deficiency induced by nivolumab in a patient with breast cancer, diabetes with hypophysitis in a patient with lung cancer, or nivolumab-induced type 1 diabetes with thyroiditis [9-11]. There is also a case of nivolumab-induced hypothyroidism associated with isolated ACTH deficiency reported previously [12]. However, in our case, multiple endocrinopathies, i.e., type 1 diabetes, ACTH deficiency, and hypothyroidism, were seen simultaneously, which is very rare. In our patient’s case, insulin therapy for type 1 diabetes occurred prior to ACTH deficiency and hypothyroidism, which made it difficult to diagnose these complications because episodes of hypoglycemia could often occur in type 1 diabetes treated with insulin other than ACTH deficiency or hypothyroidism.

Secondly, further hormone investigations should be taken into consideration when regular treatment intervention is not effective or unexplained symptoms are observed. In previous reports, there are 2 cases of endocrinopathies that developed within a month [9, 10] and 2 cases that developed a couple of months later [11, 12]. In the latter cases, new symptoms or abnormal data were found in sequence, which makes it easier to reach an early diagnosis and to provide treatment. In our case, there were persistent episodes of hypoglycemia, impaired consciousness, and fever, which could not be explained by proper treatment or examination. However, an examination provided us with a clue of complicated multiple endocrinopathies. Endocrine dysfunctions associated with cancer immunotherapies are uncommon and sometimes challenging to diagnose, but a delayed diagnosis could be fatal [13, 14].

In conclusion, it is important to keep in mind that rare endocrinopathies induced by nivolumab could possibly occur simultaneously, and further investigations of hormones are necessary and should be performed without delay.

We followed the World Medical Association’s Declaration of Helsinki. Informed consent was obtained from the patient for the publication.

The authors have no conflicts of interest to declare.

There were no funding sources.

Shoko Marshall wrote the manuscript, and all authors treated the patient, collected data, read and approved the final manuscript.