Endogenous Hyperinsulinemic Hypoglycemia Research Articles

Abstract 160: A tri prong approach in the management of insulin autoimmune syndrome

Insulin autoimmune syndrome (IAS) manifests as transient self-limiting endogenous hyperinsulinemic hypoglycemia. It is characterized by the presence of insulin autoantibodies which bind insulin and the unpredictable release of insulin from insulin-autoantibody complexes resulting in spontaneous hypoglycemia. It needs to be considered in patients with hypoglycemia (in non-diabetic individuals) to avoid unnecessary investigations and surgical interventions. Treatment of Insulin autoimmune syndrome has always been an enigma. We suggest a tri-prong approach, with the pharmacological cocktail of alpha glucose inhibitor, steroids, and diazoxide along with dietary modifications after the elimination of the culprit agent. The targeting of the three major pathogenetic mechanisms when initiated early holds the potential of earlier relief of symptoms and accelerated recovery in severe and refractory hypoglycemia.

68 Ga-DOTATATE PET/CT imaging in endogenous hyperinsulinemic hypoglycemia: A tertiary endocrine centre experience.

Literature regarding utility of 68 Ga-DOTATATE PET/CT in insulinoma localization across various subgroups [benign/malignant/multiple endocrine neoplasia-1 (MEN-1) syndrome associated] remains scarce. In this study, the performance of 68 Ga-DOTATATE PET/CT was compared with contrast-enhanced computed tomography (CECT) and 68 Ga-NODAGA-Exendin-4 PET/CT (whenever available) in an endogenous hyperinsulinemic hypoglycemia (EHH) cohort. Retrospective audit. EHH patients [N = 36, lesions (n) = 49, final diagnosis: benign sporadic insulinoma (BSI) (N = 20), malignant insulinoma (N = 4, n = 14), MEN-1 syndrome associated insulinoma (N = 9, n = 15), Munchausen syndrome (N = 2) and drug-induced hypoglycemia (N = 1)] having both preoperative imaging modalities (CECT and 68 Ga-DOTATATE PET/CT). Per-lesion sensitivity (Sn) and positive predictive value (PPV) for histopathological diagnosis of insulinoma. Sn and PPV of 68 Ga-DOTATATE PET/CT were 67.3% and 89.2%; 55% and 100%; 85.7% and 100%; and 66.7% and 77% for overall EHH, BSI, malignant, and MEN-1 syndrome associated insulinoma cohorts respectively. Despite having comparatively lower sensitivity in BSI cohort, 68 Ga-DOTATATE PET/CT localized a pancreatic tail lesion missed by other modalities. 68 Ga-DOTATATE PET/CT had comparatively higher sensitivity in malignant insulinoma than BSI cohort. 68 Ga-DOTATATE PET/CT also paved the way for successful response to 177 Lu-based peptide receptor radionuclide therapy (PRRT). In MEN-1 cases, lower PPV as compared with BSI was due to uptake in non-insulinoma pancreatic neuroendocrine tumours (Pan-NET). 68 Ga-DOTATATE PET/CT has supplemental role in selected cases of BSI with negative and/or discordant results with CECT and 68 Ga-NODAGA-Exendin-4 PET/CT. In malignant insulinoma, 68 Ga-DOTATATE-PET/CT has an additional theranostic potential. Interference due to uptake in non-insulinoma Pan-NET in MEN-1 syndrome may hinder insulinoma localization with 68 Ga-DOTATATE-PET/CT.

Hypoglycemia due to insulin autoimmune syndrome (Hirata’s disease): a rare cause of hypoglycaemia

Although the most common cause of recurrent hypoglycaemia is diabetes mellitus as patient is on antidiabetic medications which can be prevented by modification of antidiabetic doses, nutrition therapy and lifestyle modifications. Some endogenous hyperinsulinemic conditions like insulinoma, functional beta cell disorders and insulin autoimmune syndromes, hormonal deficiencies can cause serious and sometimes life threatening hypoglycaemia. So further laboratory evaluation like plasma/serum glucose levels, c-peptide levels, insulin levels, insulin antibodies and imaging studies are needed to evaluate unexplained hypoglycaemia. Here we report a case of insulin autoimmune syndrome in a 67 year old Indian male who had presented to us with multiple episodes of spontaneous hypoglycaemia. On further workup, the patient was found to have endogenous hyperinsulinemic hypoglycemia. As the patient’s abdominal imaging revealed no apparent cause of EHH, on further evaluation he came positive for insulin antibodies. Patient was diagnosed as IAS and he was given frequent small meals and complex carbohydrate diet and he had improved symptomatically. The incidence of IAS is most common in Japan and very few cases have been reported from India, so it should be kept in differential diagnosis of recurrent hypoglycaemia.

Autoimmune hypoglycaemia: a narrative review from the laboratory perspective

: Whilst hypoglycaemia is common, autoimmune causes are relatively rare. Autoimmune causes of hypoglycaemia includes both insulin autoimmune syndrome (IAS), and type B insulin resistance syndrome (TBIR). IAS typically presents with post-prandial hypoglycaemia in adulthood and is characterised by inappropriately high plasma insulin, proinsulin and C-peptide concentrations during hypoglycaemia, with C-peptide:insulin molar ratios of <1, high insulin autoantibody titres and the presence of macroinsulin. TBIR typically presents with hyperglycaemia due to insulin resistance as a result of insulin receptor antibodies. TBIR may, however, also present with endogenous hyperinsulinaemic hypoglycaemia or hyperglycaemia-hypoglycaemia depending on the activating or inhibiting action of the insulin receptor antibodies. Very rarely, autoimmune hypoglycaemia may be due to insulin antibodies raised to therapeutic insulin or insulin-binding paraproteins with purported mechanisms similar to IAS in producing hypoglycaemia. This review summarises the pathophysiology and laboratory features of IAS and TBIR, and highlights the importance of considering these diagnoses in patients with hypoglycaemia associated with non-suppressed insulin levels, to prevent unnecessary pancreatic surgery.

Diagnostic Evaluation of Hypoglycemia Due To an Insulinoma in a Deployed Infantryman: Significance of Neuroglycopenia and the Role of the Military Health System.

Insulinoma, the prototype of endogenous hyperinsulinemic hypoglycemia, is a very rare condition, with an incidence of four cases per million person-years. Its rate of occurrence in the U.S. military population is unknown. Two cases of insulinomas involving active duty service members have been published. However, there has been no reported case of an insulinoma in a deployed service member. We report the case of a 21-year-old infantryman with clinical hypoglycemia of insidious onset, manifesting with overt neuroglycopenic symptoms during his deployment as a combatant soldier, and the ultimate diagnosis of an insulinoma as the underlying cause. The series of multiple clinical evaluations and the unique circumstances leading to the formal evaluation of the patient's hypoglycemia and treatment are chronicled. The significance of neuroglycopenia and the diagnostic approach to any suspected case of hypoglycemia, the potential challenges and opportunities, and educational aspects of evaluation and management of the insulinoma are elaborated. The potential role of the Military Health System in facilitating the detection and treatment of this rare condition in the service member is discussed as well.

Investigating difficult to detect pancreatic lesions: Characterization of benign pancreatic islet cell tumors using multiparametric pancreatic 3-T MRI.

IntroductionPancreatic islet-cell tumors (PICT) often present with atypical signal-characteristics and are often missed on preoperative imaging. The aim of this study is to provide a multiparametric PICT characterization and investigate factors impeding PICT detection.Material and methodsThis is a detailed MRI analysis of a prospective, monocenter study, including 49 consecutive patients (37 female, 12 male; median age 50) with symptoms due to endogenous hyperinsulinemic hypoglycemia (EHH) and mostly negative prior-imaging. All patients received a 3-T MRI and a 68Ga-DOTA-exendin-4-PET/CT. Pooled accuracy, sensitivity, specificity and inter-reader agreement were calculated. Reference-standard was histopathology and 68Ga-DOTA-Exendin-4-PET/CT in one patient who refused surgery. For PICT analyses, 34 patients with 49 PICTs (48 histologically proven; one 68Ga-DOTA-exendin-4-PET/CT positive) were assessed. Dynamic contrast-enhanced (DCE) Magnetic Resonance Images (MRI) with Golden-Angle-Radial-Sparse-Parallel (GRASP) reconstruction, enabling imaging at high spatial and temporal resolution, was used to assess enhancement-patterns of PICTs. Tumor-to-background (T2B) ratio for each sequence and the employed quantitative threshold for conspicuity of PICTs were analyzed in regard to prediction of true-positive PICTs.ResultsEvaluation of 49 patients revealed a pooled lesion-based accuracy, sensitivity and specificity of 70.3%, 72.9% and 62.5%, respectively. Mean PICT size was 12.9±5.3mm for detected, 9.0±2.9mm for undetected PICTs (p-value 0.0112). In-phase T1w detected the most PICT (67.3%). Depending on the sequence, PICTs were isointense and poorly visible in 29–68%. Only 2/41(4.9%) PICTs showed typical signal-characteristics across T1w, T2w, DWI and ceT1w combined. 66.6% of PICTs enhanced simultaneously to the parenchyma, 17.8% early and 15.6% late. Predictor screening analysis showed number of sequences detecting a PICT, lesion size and in-phase T1w T2B ratio had the highest contribution for detecting a true-positive PICT.ConclusionThe majority of PICTs enhance simultaneously to surrounding parenchyma, present with atypical signal-characteristics and thus are poorly visible. In non-enhancing PICTs, radiologists should search for small lesions most likely conspicuous on unenhanced T1w or DWI.

The Role of Glucagon-Like Peptide 1 Receptor PET/CT With Ga-68-NODAGA-exendin in Localising an Insulinoma: Lessons From a Clinical Case

We present a clinical case highlighting the diagnostic challenges in a patient with an insulinoma. A 57-year-old lady initially presented with sweating on waking. Investigation documented a fasting blood glucose of 2 mmol/L (3.9-5.4) and the presence of anti-endomysial antibodies. On the basis of a diagnosis of Coeliac disease, the patient was commenced on a gluten free diet with apparent resolution of symptoms for 9 years. Subsequently, she re-presented with recurrent episodes of confusion which resolved with a ‘sugary’ drink. Consequently, she underwent a prolonged supervised fast: glucose 1.9 mmol/L (neuroglycopaenic symptoms), insulin 76 pmol/L (<20), c-peptide 763 nmol/L (<200) and β-hydroxybutyrate (BHB) 131 μmol/L (<2700). A diagnosis of endogenous hyperinsulinaemic hypoglycaemia resulted in radiological investigation (CT thorax/ abdomen/pelvis, MRI pancreas and endoscopic ultrasound [EUS] of pancreas) with no tumor identified. Due to persisting symptoms, in addition to dietary changes, diazoxide and octreotide were commenced. She was referred for a second opinion where a repeat 72-hour fast (at the time of hypoglycaemia symptoms) showed: glucose 2.3 mmol/L, Insulin 51 pmol/L, C-Peptide 513 pmol/L, BHB 1580 μmol/L and proinsulin 31 pmol/L (<10). Insulin antibody and sulphonylurea screens were negative. Her symptoms resolved after carbohydrate ingestion. Further imaging including a Ga-68-DOTATATE PET/CT, selective arterial calcium stimulation and hepatic venous sampling failed to localise an insulinoma. Despite pharmacological treatment hypoglycaemia continued to impede the patient’s quality of life and both octreotide and diazoxide were stopped due to side effects and minimal benefit. A glucagon-like peptide 1 receptor (GLP-1R) PET/CT scan with Ga-68-NODAGA-exendin-4 was performed and revealed uptake in a lesion in the ventral pancreatic body, suggestive of an insulinoma. A further EUS showed a corresponding 10 mm calcified area in the pancreatic body. The surgeon was unable to identify the tumor intra-operatively (macroscopically and ultrasound guided) and therefore performed a distal pancreatectomy which encompassed a 13 mm tumor. Histopathology demonstrated a 13 mm well differentiated, Grade 1 pancreatic neuroendocrine tumor (Ki67 1%) staining positively for AE1/AE3, synaptophysin, chromogranin and insulin (GLP-1R and pro-insulin staining awaited). Post-operatively, there was complete resolution of hypoglycaemia. In summary the learning points are the 9-year interval between initial presentation and confirmation of the diagnosis and the challenge of tumor localisation. There is no published evidence about gluten free diets reducing hypoglycaemia in insulinomas, but our patient described symptomatic improvement. GLP-1R are expressed in >90% of insulinomas and this case underlines the utility of GLP-1R PET/CT in insulinoma localisation.

S2754 Noninsulinoma Pancreatogenous Hypoglycemia Syndrome (NIPHS) and Severe Portein-Calorie Malnutrition; Unexpected Outcomes After Gastric Bypass Surgery

INTRODUCTION: Bariatric surgery is the most effective way to achieve a clinically significant weight loss in severely obese patients but rarely it can cause Noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS) and severe protein-calorie malnutrition which happened in our case. CASE DESCRIPTION/METHODS: 49 years old female with a history of Roux-en-Y gastric bypass (2005) admitted for altered mental status secondary to hypoglycemia ( FS 25) and multiple electrolyte abnormalities ( Na 158, K 2.5, BUN 50, Cr 2.5). She was acutely managed resulting in improvement in mental status. She endorsed continued weight loss for the last 6 months along with anorexia. Upper endoscopy and Colonoscopy did not reveal any cause. Her hospital course was complicated by recurrent episodes of hypoglycemia. Further workup raised the possibility of Noninsulinoma pancreatogenous hypoglycemia syndrome(NIPHS) for which diazoxide was started. A feeding tube was placed in the remnant stomach because of continued weight loss. The patient was followed after 2 months by the bariatric surgery team and underwent reversal of RYGB with uneventful post-op recovery. DISCUSSION: Noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS) and severe protein-calorie malnutrition are extremely rare complications after bariatric surgery. NIPHS is characterized by endogenous hyperinsulinemic hypoglycemia that is not caused by an insulinoma. Histopathology specimens have revealed islet cell hypertrophy and sometimes islet cell hyperplasia. The predominant clinical feature is postprandial hypoglycemia. Biochemical findings are similar to insulinoma which include elevated plasma insulin, C-peptide, and proinsulin concentrations. Definitive diagnosis is made by EUS guided pancreatic biopsy which might be difficult to do in RYGB patients. In case reports, octreotide, verapamil, diazoxide, and acarbose have reportedly improved hypoglycemic symptoms. In severe cases, partial or subtotal pancreatectomy is performed. Severe protein-calorie malnutrition can cause continued weight loss years after bariatric surgery. It can be managed successfully with nutritional support in most of the cases. Patients may also require a psychological evaluation and/or counseling to determine the degree to which a psychosocial etiology is involved. It is important to rule out and treat all possible underlying mechanical and behavioral causes before considering a surgical revision such as the lengthening of the common channel or surgical reversal.

SAT-679 Autoimmune Hypoglycemia: A Treatment Challenge

Background: Upon evaluation of patients with recurrent hypoglycemia, both exogenous and endogenous causes should be excluded. Among endogenous hyperinsulinemic hypoglycemia (EHH) pathologies, Insulin Autoimmune Syndrome (IAS), even though extremely rare, must be considered. Most cases of IAS have been reported in the Oriental population, mostly Japanese. No gold standard of care for this condition has been established. Clinical Case: This is the case of an 82 year-old obese female patient with dyslipidemia, obstructive sleep apnea, and osteoarthritis that comes to the Endocrinology clinics for evaluation due to recurrent episodes of hypoglycemia. She refers that for the last three years she had been presenting with multiple episodes of symptomatic hypoglycemia, even levels as low as 30 mg/dL, requiring multiple hospitalizations. Consequently, she refers a 15-pound weight gain because of multiple daily snacks. Home medications were simvastatin and diclofenac. She denies using insulin, sulfonylureas, other hypoglycemic agents, alcohol, or illicit substances. Abdominal MRI and PET CT scan were remarkable only for an atrophic pancreas without focal masses. Patient was hospitalized for a supervised 72-hour fast, resulting in severe hypoglycemia within 14 hours with elevated insulin levels at 46.3 uIU/mL (1.7-31.0 uIU/mL), elevated C-peptide levels at 5.79 ng/mL (0.9-4.3 ng/mL) and elevated insulin antibodies 53µU/mL (<5µU/mL). Patient showed sufficient hepatic reserve after glucagon administration as well as intact cortisol and growth hormone axis upon severe hypoglycemia. With these results, a diagnosis of IAS was made; not associated with other autoimmune diseases, or with medications with sulfhydryl groups, such as the cases already reported on literature. This condition represents a therapeutic challenge because there is no gold standard of care. Literature recognizes diverse treatment options that range from diet modification to more aggressive therapies, including plasmapheresis and immunosupressants. Our patient was managed with diet modification including frequent snacks and Diazoxide with the goal of decreasing insulin levels and inducing hyperglycemia. Diazoxide therapy achieved a steady euglycemic state and decreased insulin antibodies. Patient developed intolerable bilateral lower extremity edema and treatment was modified to complex carbohydrates, frequent snacks in the daytime and Diazoxide only at bedtime, which is the longer fasting period. Patient has remained without episodes of hypoglycemia and diabetes has not been diagnosed since starting treatment two years ago. Conclusion: Early recognition of IAS is essential in order to avoid unnecessary studies and procedures which could delay management. Although no gold standard therapy has been identified for this condition, our case report identifies Diazoxide as a compelling medical treatment.

SUN-299 Flash Glucose Sensor Monitoring for Patients with Endogenous Hyperinsulinaemic Hypoglycaemia

Flash Glucose Sensor Monitoring for patients with endogenous hyperinsulinaemic hypoglycaemiaBackground:Flash glucose monitoring systems (FGS) have recently been introduced and measure interstitial glucose using an amperometric electrochemical sensor assay, and are increasingly used to provide a convenient means to monitor levels on a minute-by-minute basis over two weeks in ambulatory patients with diabetes. Although continuous glucose monitoring systems have been previously used in patients with insulinoma,(1) to our knowledge, FGS use has only been described once previously in an adult patient with an insulinoma.(2) Here, we describe use of this system in 6 patients with confirmed endogenous hyperinsulinaemic hypoglycaemia, especially for the critical nocturnal period.Methods and patients:FGS data obtained over each 2-week monitoring was reviewed in 6 patients seen between 2018 and 2019: 5 had a biochemically proven insulinoma and 1 had Hirata’s syndrome. In 4 patients, follow-up readings were obtained after adjustment of glucose-raising medication: two on octreotide, one on diazoxide and one on diazoxide and dexamethasone.Results:Median age was 63 years (range 37–83). In the 4 patients with more than one 2-week FGS assessment comparison between first and last readings demonstrated that the average duration of hypoglycaemia (<4mmol/L) 126, 171, 173 and 282 minutes improved to 46, 128, 30 and 0 minutes, respectively. The percentage of glucose readings below target (<4mmol/L) improved from 8%, 58%, 4%, and 47% to 1%, 39%, 0%, and 0%, respectively. The mean glucose was 5.9, 3.9, 7.8, and 4.4 mmol/L, which improved to 10.9, 5.0, 7.9, and 7.5 mmol/L respectively. The lowest average glucose was nocturnal (22:00-06:00) (5.8, 3.3, 6.5, and 4.1 mmol/L) which showed significant improvement after adjustment of medications (11.3, 4.2, 7.2, and 5.7 mmol/L). At least 2 of these 4 patients had well documented impaired awareness of hypoglycaemia based on diminished classical adrenergic symptoms. Among the two patients who had only one 2-week FGS assessment, one went on to have curative successful surgery and the second patient who had Hirata’s syndrome did not have significant detectable hypoglycaemia.Conclusion:FGS is a convenient tool that may be used to monitor and adjust therapy in patients with endogenous hyperinsulinism. In carefully selected patients, FGS may allow domiciliary glycaemic management avoiding the need for hospital admission for monitoring purposes.

MON-904 Behind the Mask: The Stories of Insulinoma- a Case Series

Introduction: Insulinoma is a rare, slow growing pancreatic neuroendocrine tumor, leading to hyperinsulinemic hypoglycemia. It runs a very insidious course often masquerading as neurologic, psychological or cardiac disease. We present a series of four cases with varying clinical presentations, diagnoses and latency to diagnosis.Case Report: This is a retrospective analysis of four cases of Insulinoma diagnosed between Sep 2016 and Mar 2019. All the patients were males and aged 36, 22, 63 and 15 years respectively. Baseline characteristics, duration to diagnosis of Insulinoma, diagnosis and treatment given before definitive diagnosis and post-surgery outcomes were analyzed. All the four patients had relatively long latency to diagnosis despite frequent, spontaneous hypoglycemic episodes, longest being ten years. The patients had a neurological and/or psychiatric diagnosis prior to definitive diagnosis. The symptoms improved with consumption of food. One of the four patients was on antipsychotics for episodic abnormal behavior before the diagnosis of Insulinoma. Two of them were on anti-epileptic medications for seizures. All the insulinomas were localized with CECT without requirement for additional localization techniques. All our patients responded well to surgical resection of the tumor. All insulinomas were benign grade 1 tumors. Acanthosis nigricans regressed in all the patients post-surgery. In addition, all the patients had significant weight loss post-surgery. Two of the four patients developed diabetes mellitus and were on insulin therapy.Conclusion: A strong index of suspicion of Insulinoma is warranted while dealing with patients presenting with seizure disorders, behavioral abnormalities and neurological symptoms because the spectrum of symptoms is wide and non-specific. Seeking diagnosis is of utmost importance because of implications on treatment and prognosis.Reference:Valente LG, Antwi K, Nicolas GP, Wild D, Christ E. Clinical presentation of 54 patients with endogenous hyperinsulinaemic hypoglycaemia: a neurological chameleon (observational study). Swiss Med Wkly. 2018 Nov 18;148:w14682.

Abstract #806920: Endogenous Hyperinsulinemic Hypoglycemia in a Patient with End Stage Renal Disease (ESRD)

Abstract #806920: Endogenous Hyperinsulinemic Hypoglycemia in a Patient with End Stage Renal Disease (ESRD)

Innovative imaging of insulinoma: the end of sampling? A review.

Receptors for the incretin glucagon-like peptide-1 (GLP-1R) have been found overexpressed in selected types of human tumors and may, therefore, play an increasingly important role in endocrine gastrointestinal tumor management. In particular, virtually all benign insulinomas express GLP-1R in high density. Targeting GLP-1R with indium-111, technetium-99m or gallium-68-labeled exendin-4 offers a new approach that permits the successful localization of small benign insulinomas. It is likely that this new non-invasive technique has the potential to replace the invasive localization of insulinomas by selective arterial stimulation and venous sampling. In contrast to benign insulinomas, malignant insulin-secreting neuroendocrine tumors express GLP-1R in only one-third of the cases, while they more often express the somatostatin subtype 2 receptors. Importantly, one of the two receptors appears to be always overexpressed. In special cases of endogenous hyperinsulinemic hypoglycemia (EHH), that is, in the context of MEN-1 or adult nesidioblastosis GLP-1R imaging is useful whereas in postprandial hypoglycemia in the context of bariatric surgery, GLP-1R imaging is probably not helpful. This review focuses on the potential use of GLP-1R imaging in the differential diagnosis of EHH.

Nationwide survey of endogenous hyperinsulinemic hypoglycemia in Japan (2017-2018): Congenital hyperinsulinism, insulinoma, non-insulinoma pancreatogenous hypoglycemia syndrome and insulin autoimmune syndrome (Hirata's disease).

Aims/IntroductionWe aimed to investigate the nationwide incidence, treatment details and outcomes of patients with endogenous hyperinsulinemic hypoglycemia (EHH), including those with transient/persistent congenital hyperinsulinism (CHI), insulinoma, non‐insulinoma pancreatogenous hypoglycemia syndrome and insulin autoimmune syndrome (Hirata’s disease) in Japan.Materials and MethodsA nationwide, questionnaire‐based survey was carried out to determine the number of patients with EHH who were treated for hypoglycemia or hypoglycemia‐related complications in 2017−2018. The questionnaires were sent to all hospitals in Japan with >300 beds, and with pediatric and/or adult clinics likely managing EHH patients. The secondary questionnaires were sent to obtain the patients’ date of birth, sex, age at onset, treatment details and post‐treatment outcomes.ResultsA total of 447 patients with CHI (197 transient CHI, 225 persistent CHI and 25, unknown histology), 205 with insulinoma (118 benign, 18 malignant and 69 unknown subtype), 111 with non‐insulinoma pancreatogenous hypoglycemia syndrome (33 post‐gastric surgery HH, 57 postprandial HH, 10 nesidioblastosis and 11 unknown subtype) and 22 with insulin autoimmune syndrome were identified. Novel findings included: (i) marked improvement in the prognosis of persistent CHI over the past 10 years; (ii) male dominance in the incidence of transient CHI; (iii) non‐insulinoma pancreatogenous hypoglycemia syndrome emerging as the second most common form of EHH in adults; (iv) frequent association of diabetes mellitus with insulin autoimmune syndrome; and (v) frequent post‐treatment residual hypoglycemia and impaired quality of life.ConclusionsThe first nationwide, all age group survey of EHH showed the current status of each type of EHH disorder and the unmet needs of the patients.

MON-135 A Case of Hirata’s Disease

Introduction- Insulin Autoimmune Syndrome (IAS), also known as Hirata's disease, is a rare cause of endogenous hyperinsulinemic hypoglycemia, characterized by episodes of spontaneous hypoglycemia with high serum insulin and elevated insulin autoantibodies in the individuals who have not received exogenous insulin. Only few cases have been reported in Caucasians while there have been more than 300 cases from Japan. Given the rarity of this condition outside of Japan, here we report a case of Hirata’s disease. Case Presentation- A 59-year-old male was brought in to the emergency room with altered mental status and slurred speech. Patient's initial blood glucose was 30 and was given dextrose 10 (D10) en route with remarkable improvement in his mental status and speech and resolution of neuroglycopenic symptoms. Patient’s vital signs and physical exam was unremarkable. Basic initial laboratory workup was unremarkable. He reported no similar episodes in the past. He is not any medications known to cause hypoglycemia. ACTH, cortisol, TSH and T4 levels were normal. Sulfonylurea screen was negative. Hospital Course was complicated by recurrent, symptomatic hypoglycemic events with blood glucose as low as 37mg/dL. Initial suspected diagnosis was insulinoma and he was started on octreotide and D10 drip with continued hypoglycemia episodes postprandial. For further work up, insulin, c-peptide, proinsulin, insulin antibody were ordered during hypoglycemia episode. C-peptide was 3.7 (ULN 3.5) and insulin 156 (ULN 19) and insulin antibody > 50 (ULN 0.4). MRI abdomen revealed normal appearing pancreas and adrenal glands. Based on the presence of high titers of insulin antibodies and high insulin and relatively normal c-peptide levels accompanied by recurrent postprandial hypoglycemia’s, diagnosis of IAS was suspected and was then started on prednisone with a marked decrease in frequency of hypoglycemic episodes. Patient was discharged on oral prednisone with follow up with endocrinologist and is doing well on last outpatient follow up. Discussion- Mechanism of IAS is not well understood and is assumed to be due to antibodies against insulin that initially bind and later releases insulin asynchronously. Eighty percent of IAS patients spontaneously remit. In some individuals, IAS is associated with medications that contain ‘sulfhydryl’ group rendering insulin more immunogenic. Corticosteroids, plasmapheresis and immunosuppressants have been used to treat IAS. A diet consisting of several light meals per day, avoiding simple sugars, is recommended. Conclusion- IAS is a rare cause of hypoglycemia, and it should be suspected in non-diabetic patients with spontaneous hypoglycemia in whom there is failure to localize an abdominal tumor and who demonstrate extremely high insulin levels. Insulin autoantibodies should be tested in such patients to avoid unnecessary invasive testing and surgery.

Clinical presentation of 54 patients with endogenous hyperinsulinaemic hypoglycaemia: a neurological chameleon (observational study).

BACKGROUND Important causes of endogenous hyperinsulinaemic hypoglycaemia (EHH) in adult patients are insulinoma and adult nesidioblastosis. Data on main symptoms in EHH are scarce and controversial. We analysed main symptoms of patients with EHH in the framework of two prospective studies investigating glucagon-like peptide-1 receptor imaging. METHODS Patients were referred from secondary European endocrine centres and endocrinologists. Inclusion criteria were biochemically proven EHH (glucose <2.5 mmol/l in the presence of inadequate insulin and C-peptide levels) with neurological hypoglycaemic symptoms. Demographic characteristics and aetiologies of the patients with EHH were retrieved. Main symptoms were categorised into neurological, sympathicoadrenal (sweating, tremor, palpitation, hunger, shivering and pallor) and nonspecific other symptoms (nonspecific asthenia, weight gain, gastrointestinal symptoms and headaches). Neurological symptoms were subdivided into moderately impaired consciousness (confusion, dizziness, somnolence and delirium), visual, speech and sensorimotor impairment, severely impaired consciousness (loss of consciousness and apathy), attention deficit, seizures and personality changes. Biochemical assessment and duration of EHH at the end of a fasting test were recorded. RESULTS Fifty-four patients with full documentation were included in the analysis (74% female; mean age 54 years, range 22–84). Median duration from onset of symptoms to diagnosis of EHH was 12 months (range 0–120). Fifty (92.6%) patients had neurological symptoms, including moderately impaired consciousness (46.3%), visual, speech and sensorimotor function impairment (44.4%), severely impaired consciousness (37%), attention deficit (31.5%), seizures (16.7%) and personality change (13%). Sympathicoadrenal symptoms were present in 33 (61.1%) patients. Nonspecific other symptoms occurred in 36 (66.7%) patients. 43 patients (79.6%) suffered from symptoms of at least two different categories. CONCLUSIONS Clinical symptoms of EHH are characterised by a wide variety of mainly different neurological symptoms (“neurological chameleon”). EHH should be considered as a differential diagnosis in many neurological disorders. Trial registration numbers NCT00937079 & NCT02127541

(68)Ga-exendin-4 PET-CT for the localization of occult insulinomas: a prospective cohort study

Objective: To explore the accuracy in localizing occult insulinomas with Glucagon-like peptide-1 receptor(GLP-1R) PET-CT with (68)Ga-exendin-4. Methods: In this prospective cohort study, patients with biochemically proven endogenous hyperinsulinemic hypoglycemia and negative contrast-enhanced CT with pancreatic perfusion scans were enrolled consecutively at Department of Nuclear Medicine, Peking Union Medical College Hospital from February 2014 to June 2018.There were 37 males and 32 females, with age of (43.2±17.9)years. (68)Ga-exendin-4 PET-CT, MRI and endoscopic ultrasound(EUS) were done before elective surgery. Sensitivity, specificity, accuracy, positive predictive value(PPV) and negative predictive value(NPV) of the above imaging modalities were calculated. Results: A total of 69 patients were recruited. Thirty-two patients were diagnosed with insulinomas at histology. Four patients with positive (68)Ga-exendin-4 PET-CT findings did not undergo surgery so far. Twenty-eight patients were proven to be noninsulinoma induced hyperinsulinemic hypoglycemia. Five patients were unknown of etiology of hypoglycemia. The sensitivity, specificity, accuracy, PPV and NPV of (68)Ga-exendin-4 in localizing occult insulinomas were 96.9%(31/32), 100%(30/30), 98.3%(59/60), 100%(29/29), 96.8%(30/31), respectively.The sensitivity, specificity, accuracy, PPV and NPV of MRI were 74.1%(20/27), 9/11, 76.3%(29/38), 90.9%(20/22), 9/16, respectively. The sensitivity, specificity, accuracy, PPV and NPV of EUS were 75.0% (15/20), 2/2, 77.3%(17/22), 15/15, and 2/7. Conclusion: (68)Ga-exendin-4 PET-CT has a high sensitivity, specificity and accuracy for detection of occult insulinoma, which shows superiority to MRI and EUS.

Selective Arterial Calcium Stimulation with Hepatic Venous Sampling in Patients with Recurrent Endogenous Hyperinsulinemic Hypoglycemia and Metastatic Insulinoma: Evaluation in Five Patients

Selective arterial calcium stimulation (SACST) with hepatic venous sampling was performed in 5 patients (3 female, 2 male; age range, 53–73 y) with recurrent endogenous hyperinsulinemic hypoglycemia caused by metastatic insulinoma between January 2004 and December 2014. The biochemical results of SACST confirmed functional hepatic metastases alone (n = 3), peripancreatic lymph-node and hepatic metastases (n = 1), and occult insulinoma in the pancreatic bed (n = 1), thereby helping to guide management. SACST may be useful to determine the extent of functional metastatic insulinoma, particularly within the liver, and may provide clinicians with additional information to help guide the multidisciplinary management of patients with recurrent endogenous hyperinsulinemic hypoglycemia.

O-(2-18F-fluoroethyl)-l-tyrosine (18F-FET) uptake in insulinoma: first results from a xenograft mouse model and from human

IntroductionHerein we have evaluated the uptake of O-(2-18F-fluoroethyl)-l-tyrosine (18F-FET) in insulinoma in comparison with those of 6-18F-fluoro-3,4-dihydroxy-l-phenylalanine (18F-FDOPA) providing first data from both murine xenograft model and one patient with proved endogenous hyperinsulinemic hypoglycemia. MethodsDynamic 18F-FET and carbidopa-assisted 18F-FDOPA PET were performed on tumor-bearing nude mice after subcutaneous injection of RIN-m5F murine beta cells and on a 30-year-old man with type-1 multiple endocrine neoplasia and hyperinsulinemic hypoglycemia defined by a positive fasting test. ResultsSeven and three nude mice bearing a RIN-m5F insulinoma xenograft were respectively studied by 18F-FET and 18F-FDOPA μPET. Insulinoma xenograft was detected in all the imaged animals. Xenograft was characterized by an early but moderate increase of 18F-FET uptake followed by a slight decline of uptake intensity during the 20 min dynamic acquisition. Tumoral radiotracer peak intensity and the highest tumor-to-background contrast were reached about 5 minutes after 18F-FET iv. injection (mean SUV: 1.21 ± 0.10). The biodistribution of 18F-FET and 18F-FDOPA and their dynamic tumoral uptake profile and intensity were similar. In the examined patient, 18F-FDOPA and 18F-FET PET/CT showed one concordant focal area of well-defined increased uptake in the pancreatic tail corresponding to 11 mm histologically proved insulinoma. The SUVmax tumor to liver ratio was 1.5, 1.1 for 18F-FDOPA, 1.1, 1 for 18F-FET at early (0-5 min post injection) and delayed (5-20 min post injection) PET/CT acquisition, respectively. Despite the relatively low tumoral uptake intensity, insulinoma was clearly identified due to the low background in the pancreas. At the contrary, no 18F-FDOPA or 18F-FET tumoral uptake was revealed on whole-body PET/CT images performed about 30 min after radiotracer administration. Note of worth, the dynamic uptake pattern of 18F-FET and 18F-FDOPA were similar between human insulinoma and mice xenograft tumor. Conclusion18F-FET PET compared equally to 18F-FDOPA PET in a preclinical RIN-m5F murine model of insulinoma and in one patient with insulinoma-related hypoglycemia. However, in both cases, the tumoral uptake intensity was moderate and the tumor was only visible until 20 min after radiotracer injection. Hence, caution should be taken before asserting the translational relevance of our results in the clinical practices. However, the structural analogies between 18F-FET and 18F-FDOPA as well as the limited pancreatic uptake of 18F-FET in human, encourage evaluating 18F-FET as diagnostic radiotracer for insulinoma detection in further prospective studies involving large cohorts of patients.

MANAGEMENT OF ENDOCRINE DISEASE: Pathogenesis and management of hypoglycemia.

Glucose is the main substrate utilized by the brain and as such multiple regulatory mechanisms exist to maintain glucose concentrations. When these mechanisms fail or are defective, hypoglycemia ensues. Due to these robust mechanisms, hypoglycemia is uncommon and usually occurs in the setting of the treatment of diabetes using glucose-lowering agents such as sulfonylureas or insulin. The symptoms of hypoglycemia are non-specific and as such it is important to confirm hypoglycemia by establishing the presence of Whipple's triad before embarking on an evaluation for hypoglycemia. When possible, evaluation of hypoglycemia should be carried out at the time of spontaneous occurrence of symptoms. If this is not possible then one would want to create the circumstances under which symptoms occur. In cases where symptoms occur in the post absorptive state, a 72-h fast should be performed. Likewise, if symptoms occur after a meal then a mixed meal study may be the test of choice. The causes of endogenous hyperinsulinemic hypoglycemia include insulinoma, post-bariatric hypoglycemia and noninsulinoma pancreatogenous hypoglycemia syndrome. Autoimmune hypoglycemia syndrome is clinically and biochemically similar to insulinoma but associated with high levels of insulin antibodies and plasma insulin. Other important causes of hypoglycemia include medications, non-islet cell tumors, hormonal deficiencies, critical illness and factitious hypoglycemia. We provide an overview of the pathogenesis and management of hypoglycemia in these situations.