Abstract
Background: Checkpoint inhibitors, immunomodulatory antibodies that are used to enhance the immune system, have substantially improved the prognosis for patients with advanced malignancy like melanoma and lung cancer. Despite important clinical benefits, checkpoint inhibition is associated with a unique spectrum of side effects termed immune-related adverse events (irAEs). IrAEs include dermatologic, gastrointestinal, hepatic, endocrine, and other less common inflammatory events. Among them is endocrine toxicity, most commonly targeting the thyroid, pituitary, or adrenal glands. New-onset diabetes mellitus has been reported in only around 1% of patients in a recent study.
Although rare, fulminant and even fatal toxicities may occur with immune checkpoint inhibitors, and therefore, prompt recognition and management is important. Here we are going to present a patient with new onset Insulin dependent Diabetes mellitus secondary to immunotherapy.
It usually presents with diabetic ketoacidosis (DKA) and follows a rapid course. Awareness and prompt management are therefore key.
History and investigations:62 year old lady diagnosed with Right Uveal melanoma more than 2 years ago and was treated with Enucleation followed by Rt prosthetic eye. Subsequently patient developed metastatic melanoma with subcutaneous lesion in right paravertebral region, right humoral head and right gluteal muscle. It was unclear whether patient had metastatic uveal or cutaneous melanoma. Other PMH includes were Hypertension and Anxiety.Patient was started on Ipilimumab (CTLA-4 inhibitor) and Nivolumab (PD1 inhibitor) 6 months ago, and Ipilimumab was stopped 8 weeks ago due to side effects but continued with Nivolumab. Other current medications were Amlodipine 10 mg once daily and AmitriptylinePatient was complaining of extreme fatigue last one week and was diagnosed with Hypothyroidism with TSH >100 mIU/L (Normal 0.27-4.2) and FT4 5.4 pmol/L (Normal 12.0-22.0), subsequently patient was started on Levothyroxine 50 mcg once daily.Patient presented to emergency department with polyuria and polydipsia last 5 days and also blurred vision for last 3 weeks. Patient did not notice any recent weight loss and had widespread pain, worse on skin lesions and hip joints but did not had any other specific complaints.Patient was current smoker with more than 40 pack year history and was taking 25 units of Alcohol per week for many years. Patient did not had any significant family history including any history diabetes in the family.On examination, patient was clinically dry with capillary refill time was 5 seconds.Investigations showed-Venous blood gas-Blood Glucose - Hi (mmol/L out of range), later 22.7 mmol/LPh- 7.291, PCO2 6.14 kPa, HCO3 19.3 mmol/L, Lactate 2.2 mmol/LBlood ketones- Hi (mmol/L out of range), later >7 mmol/L
Other investigations showed-Na 131 mmol/L (Normal 135-145), K 5.4 mmol/L (Normal 3.5-5.1), Urea 7.1 mmol/L (Normal 1.7-8.3)Creatinine 139 umol/L (Normal 49-92)Bilirubin 12 umol/L (Normal 0-20), ALT 56 IU/L (Normal 10-35), ALP 157 IU/L (Normal 35-104)Amylase 59 IU/L (Normal 28-100), Albumin 48 g/L (Normal 34-50), Adjusted Calcium 2.56 mmol/L (Normal 2.2-2.6)9 am Cortisol 826 nmol/L (Normal 133-537), ACTH 28 ng/l (Normal 7.2-63.3)FSH 78.7 IU/L (Normal 25.8-134.8), LH 37.6 IU/L (Normal 7.7-58.5)IGF1 9.6 nmol/L (Normal 3.5-32.0), Prolactin 476 mIU/L (Normal 102-496)HbA1C 10.6% / 93 mmol/mmol (Normal 20-42)Serum Anti-GAD titre- 5 IU/L (Normal 0-10)
Patient was started on treatment for Diabetic Ketoacidosis (DKA) with intravenous fluid and also fixed rate Insulin infusion according to protocol. Patient responded well to treatment and biochemical profile improved with initial treatment, subsequently patient was started on regular basal bolus Insulin regime with the help from the diabetes team.
Discussion:Here we have presented a case with new onset Insulin dependent Diabetes Mellitus induced by immune checkpoint inhibitor. This kind of Diabetes progress rapidly to severe insulin deficiency compared to spontaneous Type 1 Diabetes, frequently patient present with DKA and do not go into remission. As this condition can develop rapidly, it is suggested that glucose level is to be monitored regularly and also to check HbA1C prior to initiating the immunotherapy. Their management requires complex Insulin regime to get good glycaemic control and add significant comorbidity along with the underlying cancer. The exact pathophysiologic mechanism and predictive biomarkers have not yet been established. The end result is permanent Insulin dependence. In future better characterization and further study is required to improve diagnosis and management, also to follow the natural history of this condition.
Reference:
1) Kotwal A, Haddox C, Block M, et alImmune checkpoint inhibitors: an emerging cause of insulin-dependent diabetesBMJ Open Diabetes Research and Care 2019;7:e000591. doi: 10.1136/bmjdrc-2018-000591
2) Immune checkpoint inhibitors and type 1 diabetes mellitus: a case report and systematic review.de Filette JMK1, Pen JJ2, Decoster L3, Vissers T4, Bravenboer B1, Van der Auwera BJ5, Gorus FK5, Roep BO6,7, Aspeslagh S3, Neyns B3, Velkeniers B1, Kharagjitsingh AV1,
CANDIED: A Pan-Canadian Cohort of Immune Checkpoint Inhibitor-Induced Insulin-Dependent Diabetes Mellitus
