Endogenous Hyperinsulinemic Hypoglycemia Research Articles

P-25 Unusual cause for spontaneous hypoglycemia: Hirata's Disease in Iraqi patient

Abstract Introduction Hirata's Disease, is a rare condition characterized by episodes of spontaneous hypoglycemia associated with hyperinsulinemia with positive insulin autoantibodies. Hypoglycemia is common in patients with diabetes mellitus especially those who are taking insulin therapy or insulin secretogogues oral medications but spontaneous hypoglycemia is rare and there is no clear figures about those patients in Iraq. We receive a lot of persons claim to have hypoglycemia but most of them fail to fulfill the Whipple triad. Although endogenous hyperinsulinemic hypoglycemia especially insulinoma is very rare condition, it is still concern for endocrinologist in patients presented with presumed hypoglycemia. Clinical Case A 43 year old female presented with frequent fainting attacks over several weeks. She has no past medical history a part of localized areas of vertigo for which she received no systematic treatment. Initial medical evaluation was unremarkable but with documented hypoglycemia below 40 mg/dl. She has normal heart, brain, kidney, liver, thyroid and adrenal function. She has multiple emergency admissions treatment with glucose infusion. She gains more weight as she eats more to avoid hypoglycemia. Her specific lab during the attack shows high serum insulin level (141.10 mIU/ml) with high C-peptide 18.55 ng/ml Work up for insulinoma shows normal MRI abdomen, normal endoscopic ultrasound and negative PET Gallium 68 scan. There are no previous reports of Insulin autoimmune syndrome in Iraq. The insulin autoantibodies in this patient were very high (more than 300.00 U/ml) which highly suggestive of this syndrome after excluding other factors that may cause elevation of these autoantibodies. Patient condition persist for about eight months and was advised for small multiple meals and diazoxide was not used much because it is not available in Iraq widely. Her condition resolved spontaneously after one year with dietary modifications. Conclusion Hirata syndrome is very rare but important cause of spontaneous hypoglycemia that should not be ignored. Up to our knowledge this is the first documented case in Iraq.

Evaluation of plasma cortisol during fasting test in patients with endogenous hyperinsulinemic hypoglycemia. Fifteen years experience

BackgroundEndogenous hyperinsulinemic hypoglycemia (EHH) is a rare clinical condition. The aim of this study was to evaluate baseline plasma cortisol concentration and its concentration during hypoglycemic crisis in fasting tests (FT) performed in our center. Secondarily, the aim was to establish the relationship between baseline cortisol and the time of evolution of EHH. Material and methodsA retrospective, observational, descriptive study was carried out which included patients with hypoglycemic disorder with positive FT. ResultsOf a total of 21 patients, 16 presented insulinoma, 1 nesidioblastosis, 2 malignant insulinoma and 2 EHH without pathological diagnosis. The time from the onset of symptoms to diagnosis was 2 years (Q1=1.5–Q2=5.5). The comparison between median baseline cortisol (BC)=11.8 mcg/dl (nmol/L 340.68) (Q1=9–Q3=14.1) and median cortisol during hypoglycemic episode (HC)=11.6 mcg/dl (nmol/L: 303.44) (Q1=7.8–Q3=16.1) showed no differences (Z=−0.08; P>.05). When correlating BC with HC, no significant relationship was observed (r=0.16; P>.05). When correlating the glycemic value in the crisis and the HC, a slight negative trend was found (r=−0.53; P=.01). In addition, we found that recurrent hypoglycemic disorder is associated with lower baseline cortisol values ​​the longer the time of its evolution. ConclusionWe confirmed that cortisol values ​​remain low during hypoglycemic episodes, reinforcing the hypothesis of lack of response of this counterregulatory hormone in cases of recurrent hypoglycemia.

Circularity of islets is a distinct marker for the pathological diagnosis of adult non-neoplastic hyperinsulinemic hypoglycemia using surgical specimens

BackgroundAdult non-neoplastic hyperinsulinemic hypoglycemia (ANHH), also known as adult-onset nesidioblastosis, is a rare cause of endogenous hyperinsulinemic hypoglycemia in adults. This disease is characterized by diffuse hyperplasia of pancreatic endocrine cells and is diagnosed by a pathological examination. While diagnostic criteria for this disease have already been proposed, we established more quantitative criteria for evaluating islet morphology.MethodsWe measured the number, maximum diameter, total area, and circularity (representing how closely islets resemble perfect spheres) of islets contained in representative sections of ANHH (n = 4) and control cases (n = 5) using the NIS-Elements software program. We also measured the average cell size, percentage of cells with enlarged nuclei, and percentage of cells with recognizable nucleoli for each of three representative islets. We also assessed the interobserver diagnostic concordance of ANHH between five experienced and seven less-experienced pathologists.ResultsThere was no significant difference in the number, maximum diameter, or total area of islets between the two groups, even after correcting for these parameters per unit area. However, the number of islets with low circularity (< 0.71) per total area of the pancreatic parenchyma was significantly larger in ANHH specimens than in controls. We also found that the percentage of cells with recognizable nucleoli was significantly higher in the ANHH group than in the controls. There were no significant differences in the average cell size or the number of cells with enlarged nuclei between the groups. The correct diagnosis rate with the blind test was 47.5% ± 6.12% for experienced pathologists and 50.0% ± 8.63% for less-experienced pathologists, with no significant differences noted.ConclusionsLow circularity, which indicates an irregular islet shape, referred to as “irregular shape and occasional enlargement of islets” and “lobulated islet structure” in a previous report, is a useful marker for diagnosing ANHH. An increased percentage of recognizable nucleoli, corresponding to “macronucleoli in β-cells,“ has potential diagnostic value.

SAT139 Non-insulinoma Pancreatogenous Hypoglycemia Syndrome In A Patient With 1p36 Deletion Syndrome

Abstract Disclosure: E.D. Auckley: None. M.A. Arosemena: None. L. Philipson: None. Background: 1p36 deletion syndrome comprises a phenotypic presentation that includes central nervous system, cardiac, and craniofacial anomalies. There has been no report of associated hypoglycemia with this syndrome. Nesidioblastosis, also known as non-insulinoma pancreatogenous hypoglycemia syndrome (NIPHS), is understood as a rare condition defined by diffuse pancreatic hypertrophy with subsequent hyperinsulinemic hypoglycemia. Diagnosis requires serologic workup consistent with endogenous hyperinsulinemic hypoglycemia, intraarterial calcium stimulation positive for inappropriately elevated insulin secretion, and imaging studies without identified masses. Clinical Case: A 21-year-old female with 1p36 deletion syndrome (seizure disorder, cerebral palsy, vision loss and heart failure) was admitted to the hospital due to persistent falls. On admission vital signs were within normal limits, and physical exam revealed a thin non-verbal patient without significant other findings. During hospitalization and prolonged fasting periods of approximately 14-18 hours related to poor appetite she developed several episodes of hypoglycemia with serum glucose as low as 57 mg/dl. As patient was non-verbal at baseline, symptoms of hypoglycemia such as sweating, lightheadedness or shakiness were not confirmed. Even when she started to eat, hypoglycemic events continued to occur. Dextrose containing fluids (Dextrose 5% and later 10%) were added to try to maintain blood sugars within the normal range. Nevertheless, she continued to develop hypoglycemia. Endocrinology service was consulted and recommended to obtain a critical sample. A critical sample revealed serum glucose of 59 mg/dl, insulin level of 20.6 mcU/mL, proinsulin of 33 pmol/L, and beta-hydroxybutyrate of &amp;lt;0.10 mmol/L. Insulin antibodies was negative. Adrenal insufficiency was unlikely due to a normal 9 am cortisol level of 13.7 ug/dl. Due to the presence of hyperinsulinemic hypoglycemia further workup was conducted. A CT of the abdomen with a pancreatic protocol and 68Ga-DOTATATE PET/CT scan was negative for a pancreatic mass. Endoscopic ultrasound did not reveal a clear pancreatic mass either. This was followed by a calcium stimulation test which showed a two-fold increase in insulin levels in all 3 catheterized pancreatic territories. In the absence of a discrete mass, non-surgical management was recommended. For hypoglycemia management patient was started on octreotide injections with resolution of hypoglycemia. Prior to discharge she was switched to lanreotide and was discharged to continue monthly lanreotide injections. Conclusion: To our knowledge, this is the first case reported of NIPHS in a patient with a mutation in 1p36 deletion. Hyperinsulinism in the setting of diabetes has been reported in this syndrome1 but to our knowledge no cases of hypoglycemia with NIPHS have been reported. Presentation: Saturday, June 17, 2023

FRI362 A Rare Case Of Coexisting Pancreatic Neuroendocrine Tumor And Nesidioblastosis

Abstract Disclosure: N. Mon: None. L.K. Tanwani: None. B. Martin: None. C. Scoggins: None. S.L. Mokshagundam: None. Introduction: Nesidioblastosis is a rare cause of endogenous hyperinsulinemic hypoglycemia in adult population. Pancreatic neuroendocrine tumors (NET) are also uncommon among pancreatic tumors. We report a case of a young man who presented with documented Whipple triad and was initially found to have pancreatic cyst. Further evaluation revealed concomitant pancreatic NET and adult nesidioblastosis. Case Report: A 36-year-old Caucasian male with history of anxiety, bipolar, and seizure disorder presented with witnessed seizures and was found to have blood glucose (BG) &amp;lt; 20 mg/dl. He reported recurrent hypoglycemia for 3 years with recent 4-5 ER visits for hypoglycemic seizures. Only medications he was taking were keppra and clonazepam. Physical exam was unremarkable. He was evaluated in Endocrine Clinic and a 72 Hour fast was performed. During the 72 hours fast his BG dropped to 48 mg/dl after 12 hrs. Insulin 16.1 uIU/mL, C peptide 3.02 ng/mL, Proinsulin 60.1 pmol/L, beta-hydroxybutyrate 0.08 mmol/l. BG increased to 116 mg/dl in 30 minutes after 1 mg glucagon injection. Other labs results were: 3PM cortisol 6.6 (7.0-25.0ug/dl), albumin 4.4 mg/dl, HbA1c 5.2%, Alcohol &amp;lt; 5ng/dl, negative urine toxicology screen. CT abdomen without contrast showed a 1.3 cm cyst in the tail of pancreas. Endoscopic ultrasonography revealed a round mixed solid and cystic mass (18x17 mm) with well-defined borders identified in the pancreas tail. The remainder of the pancreas was unremarkable. FNA of the cyst reported findings consistent with a well-differentiated neuroendocrine tumor. He underwent robotic enucleation of distal pancreatic lesion. Postoperative period was uneventful until 2 weeks after procedure when he again started having neuroglycopenic symptoms with lowest BG of 50 mg/dl in the fasting state. He was initiated on diazoxide 50 mg 3 times daily and then 100mg 3 times daily. He continued to have hypoglycemic episodes. Prednisone 10 mg was added at bedtime while waiting for surgery. He underwent distal 80 % pancreatectomy and splenectomy. Hypoglycemia resolved after the surgery. The final pathology was a well-differentiated NET WHO grade I with background neuroendocrine cell hyperplasia/nesidioblastosis. Conclusion: Endogenous hyperinsulinemic hypoglycemia is a rare disorder with nesidioblastosis being the important cause in children and insulinoma in adults, representing a spectrum of pathologic beta cell proliferation. There are very few reports of coexistence of both conditions in adults. Our patient also had an unusual type of insulinoma as it was cystic. The simultaneous occurrence of the two lesions offers significant challenges in diagnosis and management. The mainstay of treatment is surgical resection of insulinoma with localization of insulin hypersecretion; however, how much to remove in nesidioblastosis is still unclear. Presentation: Friday, June 16, 2023

THU390 Case Report On Hirata Syndrome: A Rare Cause Of Hypoglycemia

Abstract Disclosure: M. Pranala: None. V. Kuttiyil Oommen: None. V. Sanker: None. S. Vallabhaneni: None. K. Ajith: None. A. Thomas: None. Introduction: Hirata's disease, also known as insulin autoimmune syndrome (IAS), is a rare cause of hypoglycemia that is characterized by episodes of spontaneous hypoglycemia and insulin autoantibodies in patients who have not received exogenous insulin. IAS has been associated with rheumatoid arthritis and Graves' disease in 96% of Japanese IAS patients, and it has also been associated with other autoimmune disorders like Graves' disease. Case History: We report a case of 73-year-old male presented with the complaints of episodes of profuse sweating, palpitation and numbness over his head. Patient was initially treated symptomatically and since the symptoms were not resolving further evaluation was done. Two hourly GRBS, c- peptide, insulin levels and serum cortisol of our patient was monitored. Patient had extremely high serum insulin levels. Serum insulin antibodies level was also high (&amp;gt;300 U/ml). CT abdomen ruled out pancreatic pathology. It has been speculated that hypoglycemia occurring in IAS is due to dissociation of insulin from its antibodies in the post absorptive state. Our patient was diagnosed with IAS based on the criteria of Hirata. The age at onset, sex, and duration of hypoglycemic attacks, outcome or treatment, medication taken prior to the onset of IAS and background disease were all taken into consideration. In our patient, hypoglycemia occurred spontaneously in the post-absorptive state 4–6 hours after meal rather than after a 72-hour fast test. Extremely high levels of insulin (&amp;gt;200 µIU/mL) and Serum insulin antibodies found to be &amp;gt;30 U/ml were constructive in the diagnosis of IAS. The patient improved on dietary management alone consisting of frequent small meals. Conclusion: In order to facilitate early recognition and prevent unnecessary investigations, this could be the most significant syndrome in the differential diagnosis of endogenous hyper-insulinemic hypoglycemia (EHH). In such patients with a high index of suspicion, insulin autoantibodies should be examined. IAA prevents insulin to bind its receptor in the postprandial phase, possibly resulting in mild hyperglycemia; thereafter, insulin is released from the complexes irrespective of blood glucose concentrations, thus inducing hypoglycemia Presentation: Thursday, June 15, 2023

FRI080 Post Bariatric Hypoglycemia And Pregnancy: Successful Utilization Of Remnant Stomach Gastrostomy Tube Placement In Severe Refractory Hypoglycemia After Roux-en-Y Gastric Bypass Surgery

Abstract Disclosure: S.S. Habbsa: None. A. Port: None. Introduction: Post bariatric hypoglycemia (PBH) can occur following Roux-En-Y Gastric Bypass (RYGB). Due to an exaggerated glucagon-like-peptide-1 (GLP-1) response from rapid nutrient transit to the distal bowel, patients with PBH exhibit endogenous hyperinsulinemic hypoglycemia following a carbohydrate load. Severe cases can result in significantly impaired quality of life (QoL), including syncope, seizures, and nutritional deficits from restricted intake. Recently, remnant stomach percutaneous endoscopy gastrostomy (PEG) tube placement has been reported in a handful of cases as a successful long-term strategy for RYGB-PBH refractory to nutritional and medical therapy. However, there are no known outcomes in pregnancy. Case: A 25-year-old female with a history of RYGB presented with increasingly severe and frequent PBH beginning 12 months after surgery. Mixed meal testing was consistent with prandial hypoglycemia (down to 20 mg/dL) with hyperinsulinemia (C-peptide 11 [0.80 - 3.10 ng/mL], Insulin 50 [&amp;lt;23 uIU/mL]). Ultrasound was negative for pancreatic anomalies. Dietary modification and medical therapy with acarbose, diazoxide, and liraglutide were unsuccessful. 3 years after RYGB, she required hospitalization for hypoglycemic seizures, and she underwent remnant stomach PEG tube placement. Oral intake was discontinued (except for protein for comfort) and substituted with 12-hour nocturnal feeds. Her PBH diminished, and she reported significant improvement in QoL. 6 years after PEG placement, the patient became pregnant. Working closely with a dietician, she increased caloric intake by 200-250 kcal/day in the second and third trimesters. Screening for gestational diabetes with oral glucose tolerance testing was deferred given risk of PBH exacerbation, and CGM was used instead for glycemic monitoring. Intolerance to overnight feeds was remedied using concentrated enteral formulas and incorporation of short daytime tube feed boluses. She delivered a healthy baby via elective C-section. During lactation, due to concern for food protein allergy, she was transitioned to a non-dairy non-soy-based feeding regimen. She returned to her pre-pregnancy weight and her sugars remained stable. Conclusion: This is the first case report documenting safe and effective use of remnant stomach enteral feeds for management of severe refractory PBH post RYGB during pregnancy and lactation. Pregnancy presents a unique situation in which increased carbohydrate intake is necessary to support fetal development; however, this can be life-threatening for patients with severe PBH. Remnant stomach PEG feeds utilize the original gut without need for surgical RYGB reversal, preventing rapid nutrient transit. Long-term reversal of PBH, sustained weight loss and customizable feeding regimens support the use of remnant PEG placement for severe RYGB-PBH in the appropriate patient. Presentation: Friday, June 16, 2023

Recurrent Hypoglycemia: Endoscopic Ultrasound to the Rescue

Insulinoma is a rare pancreatic neuroendocrine tumor with an incidence of 4 per million. Ectopic insulinomas are even rarer and comprise 1-2% of these cases. In cases which have established endogenous hyperinsulinemic hypoglycemia, a high-index of suspicion must be maintained since conventional tests like Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) may miss these tumors. Endoscopic ultrasound can be utilised in localisation as it is more sensitive and specific compared to CT or MRI with an added applicability in obtaining a biopsy. However, operator skill and experience play a crucial role in identifying extra-pancreatic insulinomas.

Insulinoma with equivocal imaging.

A 55-year-old patient was admitted to our department for the management of a repetitive alteration of consciousness. Biological investigation results were consistent with endogenous hyperinsulinemic hypoglycemia. Insulinoma was therefore suspected. Abdominal computed tomography and endoscopic ultrasound showed no obvious pancreatic mass.Somatostatin receptor scintigraphy showed abnormal radioactive uptake in both the pancreatic tail and the uncinate process. Contrariwise, abdominal magnetic resonance imaging showed a unique lesion in the pancreas tail. The patient was then proposed for pancreatic surgery. Both intraoperative manual palpation and intraoperative ultrasonography of the pancreas showed a single corporal lesion of 1.5 cm. No lesion was found in the uncinate process. After a left pancreatectomy, the lesion was histopathologically confirmed to be a well-differentiated neuroendocrine tumor. The symptoms of the patient resolved almost immediately following the surgery. The follow-up is one and a half years to date. The exact preoperative localization of the pancreatic mass remains the most challenging part of insulinoma diagnostic workup. The radiologist's experience is the best warrantor to a precise localization of the tumor. 111In-DTPA-octreotide uptake in the pancreatic uncinate process may be physiological and its interpretation must, therefore, be vigilant. Manual palpation along with intraoperative ultrasonography is considered as the most effective method for the localization of insulinomas during open surgery.

Insulin autoimmune syndrome: A report of two cases

Insulin autoimmune syndrome (IAS) also known as Hirata's disease is a rare endocrine disease. It is a form of autoimmune endogenous hyperinsulinemic hypoglycemia, which develops when genetically predisposed individuals get exposed to triggering factors such as viral infection or certain medications containing sulfhydryl groups. It is important to consider IAS in the differential diagnosis of hypoglycemia as its incidence seems to be increasing worldwide. In this article, we summarize a report of two cases of IAS and their clinical manifestations, biochemical characteristics, their step-by-step diagnosis, and also prompt utilization of continuous glucose monitoring system as a monitoring tool for appropriate management. The first patient who presented with hypoglycemic episodes had recently suffered from a viral pneumonia, which probably acted as a superantigen and triggered development of IAS. The second patient also had hypoglycemic episodes, which were used to recover after intake of glucose-containing liquids. Alpha-lipoic acid containing multivitamin may have triggered the development of IAS in the second patient. The tests performed showed high serum insulin and C-peptide levels along with insulin autoantibody positivity confirming the diagnosis of Hirata's disease. Immunosuppression therapy was not required as both the patients responded well to diet modification and corticosteroid therapy. It is important to be mindful while prescribing alpha-lipoic acid-containing supplements though it has good antioxidant properties as it is presumed to be associated with increasing number of IAS cases.

A case of severe hypoglycemia after gastric bypass surgery in a woman with nonalcoholic fatty liver disease (NAFLD)

Post-gastric bypass hypoglycemia is characterized by postprandial hypoglycemia with pancreatic islet-cell hypertrophy in patients who have undergone a bariatric surgery and may be prone to hypoglycemia due to NAFLD, obesity, and impaired insulin and glucagon secretion.We present the case of a 44-year-old obese woman with NAFLD who underwent a Roux-en-Y gastric bypass and years later presented with severe hypoglycemia. She was diagnosed with endogenous hyperinsulinemic hypoglycemia and beta-cell hyperplasia.Post-gastric bypass hypoglycemia is a scenario that will be faced more often; therefore, it is important to take it into account for a timely treatment.

ODP213 Insulin Autoimmune Syndrome a rare case report

Abstract Background Insulin autoimmune syndrome IAS is cause of endogenous hyperinsulinemic hypoglycemia. Insulin autoimmune syndrome has been described with various drugs. Here we describe a case of IAS with use of Proton pump inhibitors, PPIs. Case report 49year old man came with complaints of recurrent documented hypoglycemia for the past 3months. He was a diagnosed as having Gastroesophageal reflux GERD 6 months back and has been on treatment with Pantoprazole with which his symptoms have subsided. Since past 3 months he started having episodes of excess sweating, tremulousness and palpitations. He was diagnosed as having hypoglycemia during one such episode using a glucometer value &amp;lt;60 mg/dl. After this he started monitoring his blood glucose values on glucometer and had recorded values as low as 50mg/dl, 55mg/dl, 47mg/dl. There was no specific association with meal intake. Every time his symptoms subsided with intake of diet. He was not a diabetic nor did he have any access to anti diabetic agents. With these complaints he was admitted and put on prolonged fasting, after 6 hours of fasting his blood glucose levels dropped to 42mg/dl. His critical sample revealed RBS- 42mg/dl, C peptide -15.7ng/ml (reference range 0.9-7.1ng/ml), serum insulin &amp;gt;300 µIU/ml (1.9-23µIU/ml fasting state) and serum cortisol 20.65 ug/dl(5-25ug/dl). His Sulphonyl urea screen was negative. Biochemically Endogenous hyperinsulinemia was thus proved but on imaging ultrasound examination was normal, CT scan abdomen did not reveal any pancreatic lesions. His endoscopic ultrasound also did not reveal any lesion in the pancreas. Insulin antibodies test showed positive antibodies &amp;gt;300 U/ml (reference range - &amp;lt;12U/ml). He is a known case of hypothyroidism on regular treatment. His thyroid profile was normal. There was no history of usage of methimazole, carbimazole, ALA, captopril, diltiazem, procainamide, Isoniazid, Imipenem, penicillin, Interferon, clopidogrel, gliclazide etc. He was treated with Diazoxide, Prednisolone and Acarbose. His blood glucose levels stabilized and he did not have a recurrence of hypoglycemia. Gradually he was tapered off diazoxide and prednisolone over a period of 6 months. His repeat insulin antibodies after 6 months showed 43.23U/ml (reference range&amp;lt;12). He is asymptomatic and is on follow up. IAS with PPI's is described 1 . Detailed history and physical examination did not reveal any other cause for IAS. Conclusion PPIs are commonly prescribed agents used ubiquitously. Here we wanted to highlight the importance of IAS with PPIs. There is no specific regimen used to treat IAS. Our patient showed good response to a combination of prednisolone, diazoxide and acarbose. This triple combination addresses the multiple mechanisms of hypoglycemia in IAS.

PSUN237 Hirata's Disease: A rare case of IAS in An African-American

Abstract Background Endogenous insulin autoimmune syndrome (IAS), also known as Hirata's disease, is a rare condition characterized by hypoglycemic episodes due to the presence of high titers of insulin autoantibodies. It is a form of immune-mediated hypoglycemia and can be induced with certain medications or vital infection. Often misdiagnosed or late diagnosis after extensive workup. IAS is more prevalent in people of Asian heritage, more specifically Japanese individuals, and rarely seen in Caucasians. We present a case of IAS in an African-American man.Clinical case: 51 years old African-American man with high blood pressure and marijuana use presented to the Emergency Department after a syncopal episode. He stated to have recurrent episodes of fatigue, lightheadedness, blurred vision and diaphoresis mostly within 4-5 hours post-prandial or early morning and improved with food intake. He was not taking any medication or supplementation which can cause hypoglycemia. He was found to be tachycardic with blood glucose of 25 mg/dl, treated with IV dextrose and admitted with hypoglycemia. Endocrinology service recommended to obtain insulin, c-peptide, proinsulin, hydroxybutyrate, screen for oral hypoglycemic agents during hypoglycemic episode. His blood glucose decreased to 27 mg/dL within 6 hours of fasting and work-up was completed. Significant laboratory data revealed; insulin 1000 μIU/ml (2.6-24.9), c-peptide 7 ng/dL (1.1 - 4.4), proinsulin 229.7 mmol/L (0.0-10.0), beta hydroxybutyrate acid 0.09 mmol/L (0.02-0.27), insulin receptor antibody 173 nU/ml (&amp;lt;95), screen of hypoglycemic agent Negative. Conclusion The pathogenesis of IAS has not been fully understood. Interaction of a genetic predisposition with environmental triggers leads to the production of insulin autoantibodies. Incidence of IAS is higher in Asia compared to the western countries. Medications (methimazole, alpha-lipoic acid) and viral infections (measles, mump, rubella, varicella, coxsackie, HCV) are shown to trigger the development of IAS. Although rare, IAS should be suspected in any patient presenting with hypoglycemia in order to avoid any unnecessary diagnostic and therapeutic procedure. Patients with IAS has extremely high insulin concentrations, often above 170 μIU/ml which is a rare finding in other forms of endogenous hyperinsulinemic hypoglycemia. The measurement of insulin autoantibodies is mandatory for the diagnosis of IAS since it is the only lab test that allows a reliable diagnosis. Once confirmed, the patients should be evaluated carefully in order to assess the indication to pharmacologic therapy however no study have currently compared different treatment regimens. No data regarding its survival rate are currently available. Initial clinical suspicion of IAS can avoid unnecessary costs associated with imaging examinations and/or invasive surgical procedures.

Adult-onset nesidioblastosis: a challenging diagnosis revealed by glucagon-like-peptide-1 receptor imaging

A 52-year-old female presented with recurrent episodes of fasting or post-absorptive hypoglycemia. A 72-h fasting test confirmed endogenous hyperinsulinemia. Conventional imaging was unremarkable. Selective pancreatic arterial calcium stimulation and hepatic venous sampling showed a maximum calcium-stimulated insulin concentration from several pancreatic areas, mainly the proximal splenic artery and the proximal gastroduodenal artery, suggesting the presence of one or more occult insulinoma(s) in the region of the pancreatic body. 68Ga-DOTA-exendin-4 PET/CT showed however generalized increased uptake in the pancreas and a diagnosis of nesidioblastosis was therefore suspected. The patient has been since successfully treated with dietetic measures and diazoxide. Treatment efficacy was confirmed by a flash glucose monitoring system with a follow-up of 7 months. Adult nesidioblastosis is a rare cause of endogenous hyperinsulinemic hypoglycemia. The distinction between insulinoma and nesidioblastosis is essential since the therapeutic strategies are different. 68Ga-DOTA-exendin-4 PET/CT emerges as a new noninvasive diagnostic tool for the localization of an endogenous source of hyperinsulinemic hypoglycemia. Medical management with dietetic measures and diazoxide need to be considered as a valuable option to treat patients with adult nesidioblastosis. Flash glucose monitoring system is helpful for the evaluation of treatment efficacy.

The optimal diagnostic criteria of endogenous hyperinsulinemic hypoglycemia based on a large cohort of Chinese patients.

An end-of-fast insulin level ≥ 3 µIU/ml, C-peptide level ≥ 0.6 ng/ml, and proinsulin level ≥ 5 pmol/l with end-of-fast glucose level ≤ 3.0 mmol/l have been established as the criteria for endogenous hyperinsulinemic hypoglycemia. However, all these criteria have been proposed based on patients in Western populations. This study aimed to determine the optimal criteria using a large series of Chinese patients. This retrospective study comprised 144 patients with surgically proven insulinoma and 40 controls who underwent a 72-h fasting test at the Peking Union Medical College Hospital(PUMCH) from 2000 to 2020. Receiver operating characteristic curves were used for analysis. In this series of patients, the optimal diagnostic criteria for endogenous hyperinsulinemic hypoglycemia were insulin ≥ 5.5 μIU/ml, C-peptide ≥ 0.7 ng/ml, and proinsulin ≥ 12 pmol/l with end-of-fast glucose ≤ 2.8 mmol/l; the sensitivity and specificity were 99% and 100% for insulin, 100% and 100% for C-peptide, and 93% and 100% for proinsulin, respectively. The diagnostic efficacy of the criteria based on Western populations was then tested. The sensitivity and specificity of end-of-fast insulin ≥ 3 μIU/ml, C-peptide ≥ 0.6 ng/ml, and proinsulin ≥ 5 pmol/l with end-of-fast glucose ≤ 3.0 mmol/l were 100% and 83%, 100% and 80%, and 97% and 78%, respectively. New and optimized diagnostic criteria for endogenous hyperinsulinemic hypoglycemia in Chinese populations have been proposed, and these criteria yield satisfactory accuracy.

Occult insulinoma with treatment refractory, severe hypoglycaemia in multiple endocrine neoplasia type 1 syndrome; difficulties faced during diagnosis, localization and management; a case report

BackgroundMultiple endocrine neoplasia type 1 (MEN 1) syndrome is a rare, complex genetic disorder characterized by increased predisposition to tumorigenesis in multiple endocrine and non-endocrine tissues. Diagnosis and management of MEN 1 syndrome is challenging due to its vast heterogeneity in clinical presentation.Case presentationA 23-year-old female, previously diagnosed with Polycystic Ovarian Syndrome (PCOS) and pituitary microprolactinoma presented with drowsiness,confusion and profuse sweating developing over a period of one day. It was preceded by fluctuating, hallucinatory behavior for two weeks duration. There was recent increase in appetite with significant weight gain. There was no fever, seizures or symptoms suggestive of meningism. Her Body mass index(BMI) was 32 kg/m2.She had signs of hyperandrogenism. Multiple cutaneous collagenomas were noted on anterior chest and abdominal wall. Her Glasgow Coma Scale was 9/15. Pupils were sluggishly reactive to light. Tendon reflexes were exaggerated with up going planter reflexes. Moderate hepatomegaly was present. Rest of the clinical examination was normal. Laboratory evaluation confirmed endogenous hyperinsulinaemic hypoglycaemia suggestive of an insulinoma. Hypercalcemia with elevated parathyroid hormone level suggested a parathyroid adenoma. Presence of insulinoma, primary hyperparathyroidism and pituitary microadenoma, in 3rd decade of life with characteristic cutaneous tumours was suggestive of a clinical diagnosis of MEN 1 syndrome. Recurrent, severe hypoglycaemia complicated with hypoglycaemic encephalopathy refractory to continuous, parenteral glucose supplementation and optimal pharmacotherapy complicated the clinical course. Insulinoma was localized with selective arterial calcium stimulation test. Distal pancreatectomy and four gland parathyroidectomy was performed leading to resolution of symptoms.ConclusionsRenal calculi or characteristic cutaneous lesions might be the only forewarning clinical manifestations of an undiagnosed MEN 1 syndrome impending a life-threatening presentation. Comprehensive management of MEN 1 syndrome requires multi-disciplinary approach with advanced imaging modalities, advanced surgical procedures and long-term follow up due to its heterogeneous presentation and the varying severity depending on the disease phenotype.

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.