Perioperative Management of a Rare Pancreatic Insulinoma Resection: Anaesthetic Challenge!

Insulinoma is a rare, mostly benign and solitary neuroendocrine tumour of the β-cells of islets of langerhans of pancreas. Clinically it presents with a classical ‘Whipple Triad’ encompassing symptomatic hypoglycemia, fasting hypoglycemia (<50 mg/dl) and immediate relief of symptoms after glucose administration. Definitive treatment is laparoscopic or open surgical excision of the tumour. We report and discuss the distinctive anaesthetic considerations and implications during perioperative period. A comprehensive approach including preoperative optimization of blood glucose levels with various drugs and dietary modifications, scrupulous hemodynamic and blood sugar monitoring with prompt initiation of dextrose infusion during surgical handling of tumour and meticulous management of rebound hyperglycemia with insulin infusion in postoperative period remains the essence for better outcome in these subset of patients.

Congenital insulin resistance in the practice of the pediatrician and pediatric endocrinologist -path to diagnosis

Introduction. Hyperinsulinemic hypoglycemia in children is most commonly due to congenital hyperinsulinism. When hyperinsu-linemia is accompanied by fasting hypoglycemia and postprandial hyperglycemia, rare syndromes of severe insulin resistance, which include Rabson - Mendenhall syndrome, should be suspected. This article provides an analytical review of current data on this rare genetic pathology and presents a clinical case of a previously undescribed combination of Rabson-Mendenhall syndrome with mutations in the insulin receptor gene INSR in the compound heterozygous state with multiple congenital anomalies of other organs.Clinical case. Patient N, 5.5 months old boy, with suspected congenital hyperinsulinism due to episodes of frequent severe hypoglycemia from the first day of life. At the age of 5 months, an episode of hypoglycemia up to 2.2 mmol/L was registered at an appointment with a pediatric endocrinologist. An examination was ordered, which found that against a background decrease in blood glucose to 1.9 mmol/L, C-Peptide level >5000 ng/mL, insulin level >300 lU/mL, cortisol - 971 nmol/L, TSH -3.88 mlU/L, free T4 - 10.53 pmol/L (10-23.2).The importance of early diagnosis of severe insulin resistance to prevent developmental disorders in children is emphasized. The issue of organizing multiple effective monitoring of a patient’s glycemia required special attention in this clinical case. Due to the features of metabolism in young children, we abandoned flash glucose monitoring systems and used a modern glucose meter with an integration program with a mobile application and the ability to generate reports for subsequent analysis as a reliable means of glycemic control.Summary. Based on the results of the genetic study in association with the clinical phenotype, age of debut, the patient was clinically diagnosed with Rabson-Mendenhall syndrome.Discussion. The paradoxical nature of glycemic fluctuations (severe fasting hypoglycemia and postprandial diabetic hyperglycemia) is quite typical for syndromes of severe insulin resistance and should draw the attention of an informed primary care physician.Conclusion. Careful attention to the symptoms of hypoglycemia, especially with a debut in the neonatal period, recurrent episodes, and the severity of the decrease in blood glycemia. If normal or elevated levels of insulin and C-peptide are detected against the background of hypoglycemia, the first thing to think about is congenital hyperinsulinism.

Metastatic Insulinoma Presenting With Post-Prandial Hypoglycemia

Background: Patients with an insulinoma, a type of pancreatic neuroendocrine tumor, typically present with fasting hypoglycemia (1). Occurrence of exclusively postprandial hypoglycemia as a result of a predominantly proinsulin-secreting metastatic neuroendocrine tumor is rare (2). Clinical Case: A 69-year-old man presented with episodes of postprandial blurry vision, sweating and confusion for the last two years that were becoming more frequent over the last several weeks. Self-monitoring of blood glucose at home revealed postprandial hypoglycemia (45-70mg/dl) and symptoms were consistent with Whipple’s triad. Continuous glucose monitoring over 14-days via Dexcom G6 showed no nocturnal or fasting hypoglycemia and revealed only postprandial hypoglycemia within one-two hours after meals. Laboratory measurements were performed at 8am in fasting state which revealed a blood glucose of 97mg/dl, insulin level 7.8 µIU/ml (2-21 µIU/ml), c-peptide 1.67 ng/ml (1.1-4.4 ng/ml) and elevated proinsulin level of 39 pmol/l (&lt;8.0 pmol/l). An outpatient fast was conducted in the clinic, and when serum blood glucose dropped to 47mg/dL (21 hours after the initiation of the fast), insulin (6 µIU/ml) and c-peptide (2.0ng/ml) levels were detectable with an elevated proinsulin (20.8pmol/L) level. CT abdomen and pelvis showed a 1.6cm hyperenhancing lesion in the distal body of the pancreas. He underwent endoscopic ultrasonography with fine-needle aspiration, confirming the diagnosis of a pancreatic neuroendocrine tumor. Distal pancreatectomy and splenectomy were performed to resect the tumor which led to resolution of his symptoms. Pathology revealed a low grade well-differentiated neuroendocrine tumor with lymphovascular invasion and regional lymph node metastases. Conclusion: Pancreatic neuroendocrine tumor should be considered in post-prandial hypoglycemia, even in the absence of fasting hypoglycemia. Measuring proinsulin is essential in the diagnostic workup of insulinoma causing hypoglycemia References: 1. Placzkowski KA, Vella A, Thompson GB, Grant CS, Reading CC, Charboneau JW, et al. Secular trends in the presentation and management of functioning insulinoma at the Mayo Clinic, 1987-2007. J Clin Endocrinol Metab. 2009;94(4):1069-73.2. Murtha TD, Lupsa BC, Majumdar S, Jain D, Salem RR. A Systematic Review of Proinsulin-Secreting Pancreatic Neuroendocrine Tumors. J Gastrointest Surg. 2017;21(8):1335-41.

Immunotherapy-Related Autoimmune Diabetes Mellitus and Exogenous Insulin Antibody Syndrome in a Patient With Metastatic Oral Squamous Cell Carcinoma

Introduction: Exogenous insulin antibody syndrome (EIAS) is a rare condition characterized by wide glycemic excursions and recurrent hypoglycemia in the presence of high insulin antibody titers. It has been described in diabetic patients treated with exogenous insulin. Programmed death ligand 1 (PD-L1) inhibitors are known to cause autoimmune diabetes mellitus, but PD-L1-related EIAS has not yet been reported to our best knowledge. Case Description: A 63 years old Caucasian man with history of recurrent oral squamous cell cancer presented to emergency room with polyuria, polydipsia, nausea, and vomiting 3 months after initiation of immunotherapy (Durvalumab and cetuximab). He had no prior history of diabetes mellitus or hypoglycemia. He was admitted to hospital for management of diabetic ketoacidosis (Anion gap of 24 mEq/L, venous blood glucose of 805 mg/dL, Venous PH of 7.12, large urine ketone, A1C of 8.9%). After a brief hospital stay, the patient was discharged home on insulin glargine and metformin. His immunotherapy was resumed after hospital discharge. When the patient was seen by Endocrinologist in the clinic, metformin was discontinued and prandial insulin lispro was added. This basal-bolus insulin regimen improved his glycemic control initially. However, without significant changes in his lifestyle or medical condition, he developed worsening postprandial hyperglycemia and recurrent fasting hypoglycemia. Up-titration of his mealtime insulin did not lower postprandial hyperglycemia but possibly worsened fasting hypoglycemia. EIAS was suspected after reviewing his continuous glucose monitoring data. Further work up at this point revealed mildly elevated glutamic acid decarboxylase antibodies (5.9 units/mL, normal range 0.5 - 5.0) and markedly elevated insulin antibody level (77.0 µU/mL, normal range &lt;5). His blood C-peptide was undetectable when his venous blood glucose was 252 mg/dl. In addition, his total insulin level (198 uU/mL) was much higher than his free insulin level (38 uU/mL) following an insulin lispro injection. The patient was diagnosed with EIAS. Switching insulin lispro to insulin aspart while he was on a different immunotherapy medication (Pembrolizumab) immediately reduced his average blood glucose and reduced his total daily insulin dosage by more than 50%. This improvement in glycemic control with insulin aspart only lasted for about 1 week. Unfortunately, the patient’s squamous cancer progressed on immunotherapy. He was referred to hospice care and passed away. Conclusion: Evaluation for EIAS would be reasonable in insulin-treated diabetic patients who develop wide glucose excursions and unexplained fasting hypoglycemia while on immunotherapy.

Abbott FreeStyle Libre Versus Dexcom G6: Detecting Disorders of Carbohydrate Metabolism in a Youthful Non-Diabetic Cohort Pilot Study

Objective: Disorders of aging develop decades prior to emerging according to evidence in the literature. Early detection and actionable intervention have tremendous potential to prevent, delay, or even reverse the onset of disease. Individual carbohydrate metabolism data inform interventions to address the progression of underlying disorders of carbohydrate metabolism. Continuous glucose monitoring (CGM) devices can be harnessed to reveal suboptimal glycemic control. In the present study, two CGM devices were used to screen for carbohydrate metabolic dysfunction in 14 individuals without a history of type 2 diabetes. Methods: The two CGM devices used in this prospective cohort study were the Abbott FreeStyle Libre and Dexcom G6. Participants concurrently wore both devices for 30 days and were instructed to maintain their usual dietary habits for the duration of the study. The optimal glucose range was defined as 70–120 mg/dL. Glucose data were compiled and analyzed to screen for metabolic abnormalities. Results: 14 non-diabetic individuals were enrolled in this study. The cohort was 50% female with ages ranging from 22–46 years (mean=31.4 years). Out of the 14 participants, 100% showed glycemic abnormalities, including hypoglycemia and hyperglycemia. Across the cohort, the Abbott FreeStyle Libre and Dexcom G6 detected fasting and postprandial values between 40–237 mg/dL and 40–279 mg/dL, respectively. Both CGM devices detected glucose values &lt;70 mg/dL and &gt;120 mg/dL in all 14 participants. The amount of time each participant spent outside the optimal glucose range was variable. Using the Abbott FreeStyle Libre, the mean percent of time that participant glucose values measured &lt;70 mg/dL and &gt;120 mg/dL were 9.1% and 4.8%, respectively. Using the Dexcom G6, the mean percent of time that participant glucose values measured &lt;70 mg/dL and &gt;120 mg/dL were 1.4% and 19.2%, respectively. Discussion: Using CGM devices, we discovered that these 14 non-diabetic individuals exhibit suboptimal glycemic control, as demonstrated by blood glucose measurements falling outside 70–120 mg/dL for all participants. In addition, the Abbott FreeStyle Libre detected fasting hypoglycemia and reactive hypoglycemic responses more often than the Dexcom G6, while the Dexcom G6 detected more postprandial hyperglycemia than the Abbott FreeStyle Libre. It is plausible that the recommended device placement contributed to these differences, with the Abbott FreeStyle Libre on the tricep and Dexcom G6 on the abdomen. These findings support the utility of CGM devices as screening tools to detect and predict disorders of carbohydrate metabolism and warrant further investigation into the variation between CGM device measurements.

Non-Fasting Hypoglycemia Secondary to Opioid Induced Adrenal Insufficiency: A Case Report

Background: A patient on chronic methadone therapy presented following a suicide attempt, was noted to have recurrent episodes of non-fasting symptomatic hypoglycemia and was diagnosed with opioid induced adrenal insufficiency (OIAI). Opioid induced endocrinopathies are underappreciated, particularly in the midst of a growing opioid epidemic in the United States. We believe this is the first reported clinical case of OIAI associated with non-fasting hypoglycemia. Clinical Case: A 33-year-old female with history of depression and heroine abuse on methadone therapy presented after a suicide attempt by methadone overdose. Home medications included 170mg of methadone daily for the past 5 years. She was afebrile, heart rate of 68, blood pressure 102/72, respiratory rate of 10, oxygen saturation 92%. On exam she was lethargic with altered mental status and had pinpoint pupils. Labs showed a normal complete blood count and metabolic panel. Urine toxicology was positive for methadone. Clinical picture improved temporarily after Narcan administration however 1 hour later she was confused again, with a fingerstick glucose of 50mg/dL and she was admitted to ICU for monitoring. In the ICU she continued to be lethargic with dizziness, nausea and headaches. She continued to have approximately 4 spontaneous episodes of hypoglycemia per day, despite having a good appetite and increased parenteral glucose administration. Blood pressure continued to be marginal, ranging from 85–100/50–60. There was no obvious source of infection. Urine sulfonylurea screen was negative. Investigations showed a morning cortisol of 2.23 ug/dL. A 250 µg ACTH stimulation test showed an inadequate response. The am basal plasma cortisol was 2.25 ug/dL with 15.28 ug/dL and 15.13 ug/dL at 30 and 60 minutes respectively (6.20–19.40ug/dL). She was diagnosed with hypoglycemia secondary to OIAI. Given the patient’s critical condition she was initially started on stress dose of hydrocortisone 80mg every 8 hours. Attempts to down titrate the methadone dose were unsuccessful. Patient’s symptoms improved and hypoglycemia subsided. She was discharged home on hydrocortisone 10mg qam & 5 mg qpm and she was continued on Methadone 170mg daily. Conclusion: OIAI is an under-recognized clinical entity with potentially serious adverse outcomes. Currently, 3% to 4% of US adults receive long-term opioid treatment. OIAI is present in 9—29% of individuals on chronic opioids. Opioids act through suppression of the HPA axis, primarily at the level of the hypothalamus, mediated through either delta or kappa receptors leading to a decrease in ACTH and cortisol secretion. Management should include decreasing and ideally discontinue opioids, along with glucocorticoid replacement until documented recovery of the HPA axis. Reference: Reference: (1)Donegan, Diane et al. Opioid-Induced Adrenal Insufficiency. Mayo Clin. Proc. 2018 93(7), 937–944.

Severe Fasting Hypoglycemia Mimicking Insulinoma in Three Patients With Insulin Autoimmune Syndrome

Insulin autoimmune syndrome (IAS) is a rare cause of hypoglycemia characterized by the presence of insulin autoantibodies (IAA) in patients without prior exposure to exogenous insulin. Differential diagnosis with other causes of hypoglycemia may be complex. We report three IAS cases with severe fasting hypoglycemia, referred to our Unit for the diagnostic workup of insulinoma. All three patients (two women and a man, age 66, 44, and 50 years) had history of severe fasting hypoglycemia leading to loss of consciousness along with weight gain. Both insulin and C-peptide were high, but their levels varied greatly among patients, ranging from 24 to 1500 μU/ml (n.v. &lt;16.3) and from 11 to 27 ng/mL (n.v. &lt; 4,2), respectively. Imaging studies for insulinoma were negative. In all patients, evidence of elevated IAA (ranging from 310 to 660 UA, n.v. &lt; 5) allowed diagnosis of IAS. Two patients were taking alpha lipoic acid, a sulphydryl compound consistently associated to IAS, while in the other the HLA-DRB1*0403 haplotype, conferring susceptibility to IAS, was detected. Continuous monitoring glucose (CGM) (iPro2; Medtronic Diabetes, CA, USA) showed in all patients the presence of prolonged hypoglycemia (with time spent with blood glucose below 54 mg/dL ranging from 9 to 20% of total monitoring time), and in one case the coexistence of high glucose levels after meals. One patient responded well to diazoxide treatment, while the others required both chronic steroid therapy and the use of plasmaphereses. Conclusion: Clinical manifestations of IAS vary widely among patients, without a direct correlation between symptoms severity and levels of both insulin and IAA; prandial hyperglycemia may also be present, leading to increases in glycated hemoglobin. Our patients displayed severe fasting hypoglycemic attacks that initially posed the suspicion of insulinoma. The assessment of IAA is thus mandatory in cases of fasting hypoglycemia, before proceeding to more expensive and probably unnecessary diagnostic and therapeutic procedures. CGM is a useful tool in evaluation and management of IAS, allowing the assessment of hypoglycemia duration and the detection of the wide glycemic variability secondary to the complex mechanism of insulin binding to IAA.

An Atypical Presentation of a Patient With Postprandial Hypoglycemic Induced Seizures

Background: Insulinomas are exceptionally uncommon pancreatic islet cell neuroendocrine tumors. Typically, insulinoma induced hypoglycemia occurs exclusively in the fasting state in 73 percent, reported in a retrospective analysis of 237 patients, whereas 6 percent reported only postprandial symptoms. Clinical Case: A 53-year-old female with a history of rheumatoid arthritis, obesity, and prediabetes initially admitted for new onset seizures and recurrent spontaneous hypoglycemic episodes. She experienced recurrent, symptomatic, post-prandial, hypoglycemia daily for the past 8 years. Each episode was closely associated with a high carbohydrate meal, inducing a post-prandial hypoglycemia more consistently and more profoundly than intermittent fasting. Symptoms of lightheadedness, shakiness, and seizure were exacerbated by each carbohydrate meal. Initial labs revealed serum glucose of 35 mg/dl. After recovery with dextrose infusion, a brief fasting trial less than 24 hours was performed with no recurrence of hypoglycemia. However, a mixed meal study utilizing watermelon resulted in a postprandial serum hypoglycemia of 28 mg/dl, provoking a seizure within 30 minutes. During her hospitalization, recurrent hypoglycemia was found during the postprandial period rather than intermittent fasting periods requiring dextrose infusion and octreotide. A Hypoglycemia panel sent during the initial episode was consistent with endogenous hyperinsulinism (Serum glucose=35, Insulin level=24, Proinsulin=166, C-peptide=0.9, BHB=undetectable, Sulfonurea=negative). A subsequent CT of the abdomen/pelvis revealed a mass associated with the pancreatic tail, measuring 4.1 x 4.4 x 5.2 cm concerning for pancreatic malignancy. A fine needle aspiration followed by a distal pancreatectomy and splenectomy with histopathological and immuno-histochemical evaluation confirming a well differentiated (grade 1), 5.0 x 4.5 x 3.0 cm, neuroendocrine tumor (insulinoma). Her recovery, post-operatively, was complicated by an intraabdominal abscess, left pleural effusion, necessitating insulin therapy for hyperglycemia believed to be secondary to morbid obesity, weight gain, and insulin resistance. Hypoglycemic symptoms resolved, blood glucose normalized, and insulin therapy was weaned over the following 3 months and she remains on metformin to date with no evidence of recurrence. Conclusion: Although rare, an insulinoma should be considered in the differential diagnosis of any individual with recurrent episodes of frequent symptomatic hypoglycemia. The classical clinical manifestation of an insulinoma is a fasting hypoglycemia, with distinct episodes of autonomic symptoms. However, postprandial symptoms have been reported with increasing frequency. Here we present a case of surgically confirmed insulinoma with predominantly post-prandial hypoglycemia.

Metastatic Insulinoma Presenting After Bariatric Surgery in a Patient Subsequently Diagnosed With MEN 1

Background: Hypoglycemia is a recognized complication of bariatric procedures due to changes in the gut hormonal milieu. Possible causes of hypoglycemia include dumping syndrome, nesidioblastosis and rarely insulinoma. MEN1 is a heritable disorder characterized by the occurrence of parathyroid, anterior pituitary and pancreatic islet cell tumors. Clinical Case: A 48 yo female with HTN, depression, PCOS, primary hyperparathyroidism s/p 3.5 gland parathyroidectomy 2008, facial angiofibroma 2011, obesity s/p gastric sleeve 2018, and a history of DMT2 presented with frequent episodes of hypoglycemia. DMT2 was diagnosed in 2003, but all DM drugs were withdrawn shortly after sleeve gastrectomy. One year after surgery, she started to develop primarily fasting hypoglycemia in the 40-50 mg/dl range confirmed on CGM. Symptoms included perioral numbness, diaphoresis and confusion which resolved with glucose tablets. She reported a 7 kg weight regain due to eating every 2 hours to minimize episodes but symptoms progressed. Family history was significant for HTN and DM. A 72 hour fast confirmed hyperinsulinemia with symptomatic hypoglycemia at a serum glucose of 37 mg/dl, a suppressed ß-hydroxybutyrate of 0.6 mmol/L, elevated proinsulin 7.7 ρmol/L and inappropriate normal c-peptide 0.8 ng/mL. The oral hypoglycemic panel was negative. A pancreatic protocol CT revealed a 1.2 cm heterogeneous arterial enhancing lesion in the body of pancreas, a 0.6 cm focus in the tail of pancreas, a 1.6 cm enhancing lesion in the liver and a 1.4 cm abdominal wall mass. Genetic testing was positive for MEN-1 and additional biochemical evaluation including VIP, gastrin and glucagon was negative. A pituitary MRI was unremarkable. She underwent an ex-lap, partial hepatectomy, distal pancreatectomy, splenectomy, and resection of the duodenal mass. The pancreas had multiple NETs, largest was 1.6 cm and stained positive for insulin. The liver mass demonstrated a metastatic well differentiated NET. The 1.7 cm duodenal mass was consistent with a leiomyoma. All surgical margins were negative, but focal lymphovascular and perineural invasion was identified with negative lymph nodes (0/27). She was diagnosed with a metastatic insulinoma with histopathology revealing a well differentiated neuroendocrine tumor G1, &lt;1mitosis/2mm2, Ki-67 less than 3%, stage pT1N0M1. Hypoglycemia resolved post-operatively. Conclusion: Hypoglycemia predominantly in the fasting state, worsening shortly after bariatric surgery, or refractory to dietary or medical management should be further evaluated to exclude insulinoma. Given her medical history, there was concern for MEN-1, thus prompting genetic testing. Unlike with sporadic cases, there is a higher rate of recurrence with MEN-1 associated insulinoma. Highly unusual is also the finding of metastatic disease, occurring only in 4- 14% of all insulinoma cases.