ACRT Journal

Introduction

For several decades now, pancreatic cancer remains one of the world’s most challenging diseases, both therapeutically and in terms of prognosis. According to the latest epidemiological data, it ranks as the 12th most common cancer and the 7th most common cause of cancer-related death worldwide [1,2]. Around 50-60% of patients show distant metastatic disease, 25-30% regional disease and only 10-15% local disease [1]. Therefore, improving the proportion of patients whose cancer is detected at an early stage, when treatment is likely more efficient, may enhance the outcome of pancreatic cancer. Combination chemotherapy is the current established first-line treatment approach for advanced pancreatic ductal adenocarcinoma (PDAC), specifically FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan and oxaliplatin), NALIRIFOX (Fluorouracil, leucovorin, liposomal irinotecan and oxaliplatin), and gemcitabine with nab-paclitaxel (GEM-NABP) [3]. Unsurprisingly, these treatments are fraught with side effects such as nausea, vomiting, myelosuppression, and more rarely, severe hyperglycaemia, which can lead to the onset of fulminant type 1 diabetes.

First reported by Imagawa et al. in 2000, and commonly diagnosed in the Asian population, fulminant type 1 diabetes (FT1D) is a subtype of type 1 diabetes mellitus (T1DM) distinguished by the swift and almost destruction of the pancreatic B-cells, whose acute onset leads to serious metabolic disorders and may threaten the patient’s life [4]. According to the literature, several studies have reported the induction of FT1D by interferon-alpha or immune checkpoint inhibitors [5,6]. Only sporadic cases have been reported on the onset of this diabetes during or after chemotherapy in different cancers [7,8]. However, its development mechanism remains unclear. Up to now, there have been no cases describing the development of FT1D in pancreatic carcinoma undergoing chemotherapy. Herein, we report a rare case of fulminant type 1 diabetes in a patient with no prior history of diabetes mellitus during treatment of pancreatic adenocarcinoma with chemotherapy.

Case Presentation

A 59-year-old patient with a history of hypertension treated with indapamide and perindopril was admitted to emergency with altered consciousness and hemodynamic instability. Three months before his admission, he had presented to the emergency with nausea and vomiting for several days. A lower bowel obstruction was diagnosed, caused by a 42 mm diameter sigmoidal lesion, which was treated by a Hartmann-type surgical procedure. Pathological analysis led to a diagnosis of high-grade invasive adenocarcinoma with local lymph node metastasis. In the extension work-up, a positron emission tomography scan (18F-FDG-PET/CT) revealed another lesion in the pancreas’s body and bone metastases in the sacrum (Figure 1). A final diagnosis of high-grade pancreatic ductal adenocarcinoma with lymph node, colonic, and bone metastases was made. Chemotherapy with FOLFIRINOX and dexamethasone was initiated, for which he has received a total of 3 courses to date.

Two days after completing his third cycle of FOLFIRINOX, the patient was found unconscious by his wife in the morning. According to her, it happened unexpectedly. At the arrival of the emergency physician, the Glasgow Coma Scale was at 3 on 15 (E1V1M1), associated with bradypnea at 8 cycles per minute. Oxygen saturation with an oximeter was not measurable. The patient had severe hypotension measured at 40/21 mmHg without compensatory tachycardia (regular sinus rhythm at 87 beats per minute on electrocardiogram). It is worth noting that the patient had expressed his refusal of any form of cardiopulmonary resuscitation and admission to intensive care, confirmed by his wife. Further assessment revealed hypothermia to 30 degrees Celsius, as well as severe hyperglycaemia (not measurable). Bearing in mind the patient’s condition, fluid resuscitation with crystalloid solutions (0.9% sodium chloride) was immediately initiated.

On admission to the hospital, the patient’s consciousness remained unchanged. The patient was placed on a 100% non-rebreathing mask and his respiratory rate was 12 cycles per minute. External rewarming with a heating blanket was undertaken on admission for his hypothermia. The patient appeared to respond slowly to fluid resuscitation but remained hypotensive after receiving the first 1000ml of 0.9% sodium chloride solution. Arterial blood gas analysis revealed mixed acidosis with a pH below 6.75, an unmeasurable bicarbonate level, hypercapnia with a pCO2 of 87 mmHg, and a lactic acid level of 4.40 mmol/L. Point-of-care blood glucose was elevated, above 847 mg/dL. There was no significant ketonuria and β-hydroxybutyrate levels were 0.9 mmol/L. After controlling potassium levels, which were moderately elevated, an intravenous infusion of rapid-acting fixed-rate insulin was started at 0.1 units/kg/hour, along with bicarbonate supplementation (100ml of 8.4% sodium bicarbonate solution, given in two doses). All laboratory results are presented in Tables 1 and 2. Additional laboratory investigations revealed stage 3 acute renal failure with hyperkalaemia of 5.6 mmol/L. Serum osmolality was significantly elevated at 445 mOsm/kg, with blood glucose at 1550 mg/dL. C-reactive protein levels were within the normal range and there were no clinical signs of infection either on urinalysis or on chest X-ray. Considering these findings, the retained diagnosis was a hyperglycaemic hyperosmolar syndrome due to new-onset fulminant diabetes mellitus after the third cycle of FOLFIRINOX, complicated by altered consciousness and respiratory acidosis. The respiratory acidosis was corrected, but there was no improvement in consciousness. The patient presented with multiple episodes of reentrant supraventricular tachycardia requiring the use of adenosine following European Resuscitation Council guidelines. Electrolyte levels were corrected. Regrettably, the patient progressed to ventricular fibrillation followed by asystole, resulting in his death without intensive resuscitation being carried out following the therapeutic limitations instituted by the patient and his wife.

Table 1: All laboratory results.

Table 2: All laboratory results.

Discussion

Several biological criteria are necessary to establish the diagnosis of FT1D: abrupt onset of ketosis or ketoacidosis, absence or reduction in C-peptide secretion, and elevation of plasma glucose with normal glycosylated haemoglobin, as in our patient (Table 1) [4]. However, our clinical presentation was slightly unusual. First, he presented with a state of severe hyperosmolar hyperglycaemia (HHS) with loss of consciousness (known as “hyperosmolar hyperglycaemic coma”), which manifested 48 hours after his third chemotherapy cycle, without any history of diabetes mellitus. Secondly, HHS is a clinical condition that arises more frequently in type 2 diabetes, while diabetic ketoacidosis (DKA) is more commonly encountered in type 1 diabetes [9].