The patient is a 54-year-old Filipino woman. She has no history of autoimmune diseases and is not on any regular medications. She is a past smoker (5 cigarettes/day) and does not consume alcohol.
The patient underwent surgery for left-sided breast cancer in February 2021 and postoperative chemotherapy was then initiated. The chemotherapy regimen consisted of intravenous peripheral 91.2 mg (60 mg/m2) of doxorubicin (Adriamycin) and 912 mg (600 mg/m2) of cyclophosphamide (AC). She subsequently developed anorexia after the third cycle of AC therapy on 7 May. She manifested polydipsia, polyuria, and weight loss. She had no recent infection or vaccination. On 11 May, the patient was brought to our hospital by ambulance after a disturbance of consciousness and was hospitalized. On admission, the patient recorded a body height of 148 cm, weight of 55.2 kg, body mass index of 25.2 kg/m2, Glasgow Coma Scale score of 8 (E2V2M4), body temperature of 36.3 °C, blood pressure of 80/56 mmHg, and a pulse rate of 108 beats per minute.
Clinical Presentation
Physical examination revealed the following: the bulbar conjunctiva was slightly pale but not icteric; there was no goitre, the skin was dry, and the skin turgor was reduced. There was no abnormality on lung and heart auscultation; the abdomen was soft and flat, and there was no lower leg oedema. Neurological examination revealed that the tendon reflexes were normal, and no pathological reflex was observed. Light and radial reflection were normal. Mental status, motor function, and sensory assessments could not be performed due to her low consciousness on admission.
Laboratory findings included increased urinary glucose and urinary ketone as well as increased blood ketone body levels. Her casual blood glucose and haemoglobin A1c (HbA1c) levels were 1661 mg/dL and 11.9%, respectively. Arterial blood gas analysis revealed a blood pH of 7.120, and the patient was diagnosed with diabetic ketoacidosis. Her anti-glutamic acid decarboxylase (anti-GAD) antibody test result was significantly positive (> 2000 IU/ml).
Patient’s Diagnosis
The patient was diagnosed with type 1 diabetes. The patient underwent testing for autoimmune thyroid disease, which can be a complication of type 1 diabetes and both anti-thyroglobulin and anti-peroxidase antibodies were negative.
The patient was administered the following therapy for Diabetic Ketoacidosis:
- 60 mL per hour of Ringer’s lactate solution and 60 mL per hour of a solution containing 35 mEq/L of Na, 20 mEq/L of K, 35 mEq/L of Cl, and 20 mEq/L of lactate
- 3.5 U/hr of intravenous (IV) insulin continuous infusion, which was adjusted according to blood glucose levels every 2 hours
- IV Famotidine 20mg once daily for stress ulcer prophylaxis
- IV Tazobactam/Piperacillin 2.25mg every 8 hourly to prevent secondary infection during intensive care unit (ICU) stay
Continuous IV insulin and IV drip infusion were stopped on Day 4 once the patient moved to the general ward. The patient was then started on Insulin degludec (Determir) 18 units before bedtime and Insulin Aspart (Novorapid) 12 units pre-breakfast, 4 units pre-lunch and 6 units pre-dinner. She was discharged on Day 18 of admission.
6 months post-admission, the dose of Insulin degludec was reduced to 16 units before bedtime. Insulin Aspart was reduced to 6 units pre-breakfast, 6 units pre-lunch, and 4 units pre-dinner. Her HbA1c and body weight improved to 6.6% and 57 kg, respectively
Learning Points
Immune checkpoint inhibitors (ICI)-induced type 1 diabetes is rare, occurring in 0.6-1.4% of patients receiving ICI. Rapid B-cell destruction can occur as early as 5 days after ICI initiation and up to several months after therapy is discontinued. 40-76% of patients with ICI-induced type 1 diabetes will present with diabetic ketoacidosis and almost all will require lifelong insulin therapy.
Risk factors of ICI-induced type 1 diabetes include1
- Dual ICI therapy (anti-CTLA-4 + anti-PD-1/PD-L1)
- Younger age
- History of T2DM and other types of diabetes
Therefore, most clinicians are aware to test blood glucose and endocrine hormones when they use ICI.
Doxorubicin and Cyclophosphamide is a commonly used combination but their use has rarely led to diagnosis of type 1 diabetes. In the present case, the HbA1c level was 11.9% on admission, while it was 5.9% before the breast cancer surgery, leading the clinicians to believe that doxorubicin and cyclophosphamide caused type 1 diabetes. Nevertheless, neither fasting blood glucose (FBS) nor HbA1c was measured after the first or the second AC therapy. Therefore, blood glucose should be monitored when administering doxorubicin and/or cyclophosphamide.
Cyclophosphamide has been documented to result in autoimmune diabetes in non-obese mice as it decreases suppressor T cells while enhancing pro-inflammatory T-helper type 1 response. At present, there have not been reported cases of Doxorubicin-induced type 1 diabetes but the probability is not ruled out in this case report. It is possible that the patient already had latent autoimmune diabetes, given that her HbA1c before therapy initiation was 5.9%.
From this case report, one might consider checking for autoantibodies known to cause type 1 diabetes prior to initiating Doxorubicin and Cyclophosphamide therapy.
References
- Miyabayashi M, Onishi S, Yoshida T, Takemoto M. A case of doxorubicin and cyclophosphamide therapy-induced type 1 diabetes: A case report. Journal of Medical Case Reports. 2023;17(1).
- Chen X, Affinati AH, Lee Y, Turcu AF, Henry NL, Schiopu E, et al. Immune checkpoint inhibitors and risk of type 1 diabetes. Diabetes Care. 2022;45(5):1170–6.
