Cause Of Hyperinsulinemic Hypoglycemia Research Articles

A tale of two sisters - delayed diagnosis of genetic hyperinsulinaemic hypoglycaemia.

Congenital hyperinsulinism is the leading cause of persistent hypoglycaemia in infants and children; however, it is uncommon to be diagnosed in adulthood. We describe the cases of two sisters who presented with hyperinsulinaemic hypoglycaemia aged 47 and 57 years old, who were subsequently diagnosed with compound heterozygous likely pathogenic variants in the ABCC8 gene, a known cause of monogenic congenital hyperinsulinism. We discuss the typical presenting features, investigation findings, and treatment strategies for patients with this condition. Congenital hyperinsulinism is a rare cause of hyperinsulinaemic hypoglycaemia diagnosed in adulthood. Clinical presentation is similar to an insulinoma, and imaging modalities may assist in differentiation. There are minimal medical therapies currently available for patients non-responsive to diazoxide (such as those with ABCC8 and KCNJ11 variants). Continuous glucose monitoring can be helpful in giving patients autonomy in managing their disease, as well as relieving anxiety and fear associated with hypoglycaemia.

Clinical Presentation, Diagnosis, and Management of Hyperinsulinemic Hypoglycemia in Adults: A Single-center Experience.

Hyperinsulinemic Hypoglycemia (HH) is a rare condition characterized by inappropriately elevated insulin levels in the presence of low glucose levels. A proper diagnostic framework is fundamental to avoid patients undergoing unnecessary diagnostic and therapeutic invasive procedures. The study aimed to assess the clinical presentation, diagnostic work-up, and treatment of a single-center cohort of patients affected by HH. We conducted a retrospective analysis of data collected from January 2000-2023. Our study included 104 patients: 81 (58% F) affected by insulinoma, 11 (91% F) by autoimmune hypoglycemia, 7 (71% M) by post-gastric surgery hypoglycemia, and 5 (80% F) by factitious hypoglycemia. HH was more frequent in females (63 F vs. 41 M, p-value 0.039). The median age at diagnosis was lower in insulinoma than in the autoimmune group (52.7 vs. 63.7 y, p < 0.001). During the hypoglycemic event, insulin and C-peptide levels were significantly higher in autoimmune hypoglycemia than in insulinoma (insulin 324.6 vs. 36.4 μU/ml, p-value 0.033; C-peptide 14.25 vs. 3.99 ng/ml, p-value 0.003). Specifically, C-peptide levels <9.6 ng/ml and insulin levels <75 μU/ml exhibited 97.3% vs. 93.4% sensitivity and 80% vs. 90% specificity for insulinoma diagnosis, respectively. Regarding insulinoma, the sensitivity of localizing imaging was 88% for Endoscopic Ultrasound (EUS), 86% for Magnetic Resonance Imaging (MRI), 82% for Computed Tomography (CT) scan, 52% for nuclear imaging, and 100% for angiography with the Doppman test. Among insulinoma patients, 79% received surgical treatment while 4% radiofrequency ablation. Symptomatic remission occurred in 100% of cases. We have confirmed insulinoma as the primary cause of HH. The autoimmune form should be suspected when insulin and C-peptide levels are markedly elevated.

SAT661 Bypass-oma Or Medication-oma: A Clinical Dilemma About Hypoglycemia

Abstract Disclosure: C.A. Perez Hernandez: None. M.J. Pesantez Borja: None. Introduction With the ongoing worldwide obesity epidemic, the number of bariatric procedures rises every year. Although complications have decreased in the last 20 years, they can result in significant morbidity and mortality. Hypoglycemia is a complication that usually occurs 1-3 years after a Roux-en-Y gastric bypass, and is caused by increased postprandial incretin secretion. Although reported incidence is 0.1%, it is likely underdiagnosed and underestimated cause of hyper insulinemic hypoglycemia. Clinical Case A 33-year-old male with history of pancreatic cancer status post partial pancreatectomy and Roux-en-Y gastric bypass performed 10 years ago, and type 2 diabetes on insulin was admitted for severe persistent hypoglycemia refractory to treatment. He stopped using insulin 6 months ago after passing out while driving 1-2 hours postprandially. Only 2 hours after starting a 72-hour fasting test, the patient had a venous blood glucose of 39 mg/dl. Laboratory results showed: C-peptide:3.3, Insulin:9.3, cortisol:2.6, BHB: 0.5 and proinsulin:3.7; and negative sulfonylurea screening. Dotatate scan was unremarkable. He has started diazoxide, acarbose, octreotide and Everolimus with no improvement to his symptoms. Plan was to repeat the work up, however, the patient refused to cooperate. He also declined a Calcium stimulation test, endoscopic US and bariatric surgery reversal. Review of his imaging studies which, showed no signs of pancreatic surgery. When re-interrogated, medical history inconsistencies were noticed. Hypoglycemia episodes occurred exclusively after being transferred out of ICU, patient was placed in a one-to-one monitoring. During the night shift, he was found injecting himself an unknown medication via PICC line and several medications were found in his room. After being confronted by staff, the Patient left the AMA only to be readmitted the same day for hypoglycemia at another institution. Conclusion Our patient was diagnosed with Munchausen's syndrome, substance abuse and depressive disorder upon evaluation by psychiatry. It was found that 4 years prior to current admission, he completed a 72-hour fasting test in another hospital, without hypoglycemia episodes. However, due to concerns for insulinoma, his oncology team was contacted who reported never having seen the patient or diagnosing with pancreatic cancer. Also, patient was found self-injecting with an unknown medication, and when confronted, he left AMA just like he did while he was under our care. History of self-harm behavior and inconsistencies in medical history may call for atypical presentations of Post Bariatric Surgery hypoglycemia and should prompt a detailed anamnesis and psychiatric assessment. This case represents a clinical dilemma and illustrates the therapeutic challenges encountered with a patient diagnosed with post bariatric surgery hypoglycemia and Munchausen syndrome. Presentation: Saturday, June 17, 2023

SAT163 Title: Adult-onset Hyperinsulinemic Hypoglycemia Due To An Activating Mutation In Glucokinase

Abstract Disclosure: S. Vaid: None. R. Ghosh: None. H. Elenius: None. C. Cochran: None. R. Chang: None. N. Nilubol: None. R. Muniyappa: None. Introduction: Glucokinase (GK), the key β-cell glucose sensor, determines the threshold for glucose-stimulated insulin secretion. Activating mutations of GK are infrequent causes (prevalence of 1.2%) of congenital hyperinsulinemic hypoglycemia (HH). Adult-onset of severe hypoglycemia due to GK-HH is extremely rare. Clinical Case: A 26-year-old well-nourished female (BMI, 27 kg/m2) with a recent history of dizziness, tremulousness, fatigue, sweating, and hunger, associated with weight gain presented for further workup. Hypoglycemia was noted, and Whipple's triad was confirmed. She had no family history of endocrine disease or hypoglycemia. Supervised fasting promptly produced symptomatic hypoglycemia with hyperinsulinemia. Laboratory studies revealed a low glucose level at 44 mg/dL; a plasma insulin level at 93 μIU/mL (&amp;lt;3 μIU/ml); a C-peptide level at 8.1 ng/mL (&amp;lt;0.6 ng/mL); pro-insulin at 266 pmol/L (&amp;lt;5 pmol/L); and beta-hydroxybutyrate &amp;lt;2.7 mmol/L. IGF2/IGF-1 ratio was 3.1 (&amp;lt;10) and renal and liver function was normal. Interestingly, a mixed meal also provoked significant hypoglycemia within an hour of consumption of a meal. Urine for sulfonylurea screen was negative, and so were anti-insulin antibodies. Imaging of the pancreas with computed tomography (CT), magnetic resonance imaging (MRI), and endoscopic ultrasound revealed a 1.2x0.8cm nodule on the superior margin of the body of the pancreas. 68Ga-DOTATATE​​ PET/CT (targeting somatostatin receptors) showed mild uptake coinciding with the nodule on the CT scan. Arteriography with calcium stimulation and venous sampling (ASVS) was non-localizing. The patient subsequently underwent laparoscopic exploration with intraoperative ultrasound (IOUS) of the pancreas followed by the enucleation of the pancreatic nodule. Histopathology of the nodule revealed a normal pancreatic tissue with no evidence of a neuroendocrine tumor. Change to multiple small meals, addition of cornstarch to diet, continuous blood glucose monitoring (CGM), diazoxide (70 mg oral, three times a day), and monthly octreotide LAR (30 mg) has allowed the patient to avoid hypoglycemia. Genetic testing by analysis of the genes known to cause hypoglycemia revealed a heterozygous GCK variant [c.1367C&amp;gt;T (p.Ala456Val), which was predicted to be a pathological mutation. This mutation is known to increase affinity for glucose, which leads to exaggerated insulin secretion. Conclusion: Our study highlights that in adults with non-insulinoma pancreatogenous hypoglycemia, genetic causes of HH should be considered in the differential diagnosis. Presentation: Saturday, June 17, 2023

Abstract #1397268: A Rare Case of Insulinomatosis in a 58-Year-Old Woman with Recurrent Symptoms of Hypoglycemia

Insulinomatosis is a rare cause of hyperinsulinaemic hypoglycaemia. The ideal management approach is not known. We present a case of recurrent hypoglycemia whose management was complicated by the pandemic. A 58-year-old woman with a family history of a mother who died of a pancreatic tumor and a personal history of congenital bilateral cataract, arterial hypertension, subclinical hypothyroidism, Child A liver cirrhosis, and subtotal pancreatectomy for hyperinsulinemic hypoglycemia in 2019 due to two insulinomas in the head and body of the pancreas. The pathological and immunohistochemical study was consistent with two pancreatic neuroendocrine tumors with Ki67: 1%, we did not have staining for insulin. She was discharged without episodes of hypoglycemia; 10 months after the operation, she presented a recurrence of neuroglycopenic symptoms during periods of fasting, which she controlled with a greater intake of food; furthermore, she recorded fasting capillary glycemia between 40-60mg/dl without symptoms. Due to the pandemic, she could not be evaluated at our center until 2022, when she was hospitalized for study. Hyperinsulinemic hypoglycemia was verified, imaging studies (CT, MRI, PET) did not show lesions in the remaining pancreatic tissue; On its own, endoscopic echocardiography described a 7-mm lesion adjacent to the splenic artery. The patient did not accept new surgery. The genetic study for MEN type 1 was negative. The subcutaneous octreotide test showed a glycemia value greater than 100mg/dL after its administration, so she was discharged with a fractionated diet and subcutaneous octreotide 25-50 ug at night. To date, she has not presented a clinical picture again. and biochemical hypoglycemia with adequate tolerance. Insulinomas are the most frequent pNETs (45%). About 10% are multiple, 10% are malignant, and 16% are associated with MEN1. Insulinomas are usually benign and managed surgically. Insulinomas that appear synchronously or metachronously, but are not associated with MEN1 are termed insulinomatosis. Diagnosis consists of documentation of hyperinsulinemic hypoglycemia, synchronous presence of β-cell micro- or macrotumors, or early recurrence of hyperinsulinemic hypoglycemia with new β-cell lesion in a history of prior insulinoma. Insulinomatosis is distinguished histologically by insulin-expressing monohormonal endocrine cell clusters (IMECCs) and tumor staining only for insulin, whereas MEN-1 associated insulinomas stain for multiple hormones. Regarding management, the first line is surgery, although in some cases total pancreatectomy did not result in a cure for hypoglycemia, so local or systemic treatment can be used (diazoxide, corticosteroids, somatostatin analogues, verapamil, and everolimus).

Insulin Autoimmune Syndrome: A Systematic Review.

Insulin autoimmune syndrome (IAS) is a rare endocrine disorder characterized by recurrent episodes of severe hypoglycemia, markedly elevated serum insulin, and positive insulin autoantibodies. In recent years, various countries have reported it one after another. It can be seen that we must pay attention to this disease. The diagnosis of IAS is challenging, requiring a careful workup aimed at excluding other causes of hyperinsulinemic hypoglycemia. High levels of insulin autoantibodies are found in patients, and C-peptide is not parallel to insulin, which could be diagnostic. IAS is a self-limiting disease with a good prognosis. Its treatment mainly includes symptomatic supportive treatment, such as adjusting the diet and using acarbose and other drugs to delay the absorption of glucose to prevent hypoglycemia. For patients with severe symptoms, available treatments may include drugs that reduce pancreatic insulin secretion (such as somatostatin and diazoxide), immunosuppressants (glucocorticoids, zaprin, and rituximab), and even plasma exchange to remove autoantibodies from the body. This review provides a comprehensive analysis of the epidemiology, pathogenesis, clinical manifestations, diagnosis and identification, and monitoring and treatment management of IAS.

A case of malign insulinoma diagnosed with liver metastasis

Abstract Introduction Insulinoma is a rare neuroendocrine tumor originating from pancreatic beta cells and is the most common cause of hyperinsulinemic hypoglycemia. Herein, a rare case of metastatic insulinoma in which many treatment alternatives were used will be presented. Clinical Case A 52-year-old male patient with no known history of chronic disease applied to us with complaints of numbness in the hands, inability to wake up in the morning and fainting. The patient, who worked as a professional referee, stated that he went to football matches with sugar in his pocket and ate sugar when he felt bad during the football matches. The patient needed to eat many times during the day. It was learned that the patient was treated with the diagnosis of transient ischemic attack and vertigo in another hospital where he applied with these complaints. In our hospital, random glucose was determined as 30 mg/dl. Prolonged fasting test was performed. Plasma glucose: 28 md/dl, insülin: 30,81 Uıu/ml, c-peptid 6,17 ng/ml were measured at 6th hour of the test. In abdominal computarized tomography, a 6.5×9.5 cm mass in the tail section of the pancreas and a subcentimetric metastatic nodular lesion in liver were detected. The patient diagnosed with metastatic insulinoma and distal pancreatectomy and liver metastasectomy operations were performed. Pathological examination showed insulinoma in the pancreas and neuroendocrine tumor metastasis in the liver (figure 1). No hypoglycemia was seen after operation. In the postoperative 24th month, fasting plasma glucose: 176 mg/dl and HBA1c: 8.6 were found and diabetes mellitus was diagnosed, insulin detemir was started. At the postoperative 36th month, a metastatic nodular lesion was detected in the liver. Fine needle aspiration biopsy was performed and in pathological examination, neuroendocrine carcinoma metastasis is seen. Octreotide LAR 20 mg/month treatment was started. In the follow-up, another metastasis was detected in two separate foci in liver so, patient's treatment was changed to lanreotide 120 mg/month. Four sessions of radiofrequency ablation were performed to the metastatic liver lesions. The patient is still being followed up by us and has no complaints of hypoglycemia. Plasma glucose values are in the normal range and Hba1c varies between 7.1–7.6%. Conclusion Although insulinoma cases are mostly benign, metastatic cases can also be seen rarely. The main treatment of the disease is surgery. Somatostatin analogues can be used in postoperative recurrence or inoperable metastatic disease. Radiofrequency ablation has an important role in local treatment.

Abstract #1319041: Hyperinsulinism-Hyperammonemia Syndrome in a Toddler With Recurrent Episodes of Loss of Consciousness

Hyperinsulinism-hyperammonemia syndrome (HI/HA) is one of the causes of hyperinsulinemic hypoglycemia in young children, which is responsive to diazoxide and protein restriction. Hypoglycemia of various etiologies in young children can lead to impaired neurological development. Early diagnosis and hence accurate management, is extremely important to prevent significant sequelae. We present a case of HI/HA, showing the importance of implementing the accurate approach for hypoglycemia in reaching the right diagnosis.

ODP284 Hyperinsulinism-Hyperammonaemia syndrome: a dive into the rare presentation and diagnostic challenges encountered in adults

Abstract Background Hyperinsulinemic-hyperammonemia, a rare form of congenital hyperinsulinemia, can seldom present in adulthood if failed to be diagnosed during infancy, enabling it to be difficult to identify, and predisposing affected individuals to neurological complications. Case A 20-year-old female with intellectual disability, seizure disorder and ornithine transcarbamylase deficiency was admitted for recurrent episodes of asymptomatic hypoglycemia. Her medications included risperidone, fluoxetine, levetiracetam, lacosamide, ferrous sulphate and acetaminophen. Physical examination including vital signs was unremarkable. Relevant labs included a fasting glucose of 46mg/dl [70-99]. Further work up of hypoglycemia revealed an IGF-1 of 215ng/dl [85-350] and AM Cortisol of 6.5mcg/dl [5-25]. Given a low AM cortisol level under stress, an ACTH stimulation test was done with appropriate response of cortisol of 24 following cosyntropin administration, ruling out adrenal insufficiency. The patient continued to have h ypoglycemia noted on several glucometer checks every 4 hours where she remained asymptomatic. She was further evaluated with a mixed meal study where no hypoglycemia was noted. A 72 -hour fast was performed which was terminated based on a venous blood sample glucose reading of 50 mg/dl confirmed after hypoglycemia was noted on a glucometer check. The labs showed elevated C-peptide levels of 4ng/ml [0.4-2], insulin of 4mIU/L [&amp;lt;25] and proinsulin level of 2.3pmol/l [3-20]. Levels of insulin and proinsulin were noted to be inappropriately normal in the setting of hypoglycemia. Beta hydroxybutyrate was low at 0.1mmol/L [&amp;lt;0.5] and glucagon inappropriately normal at 36pg/ml [50-100]. Sulfonylurea, meglitinide and autoimmune antibody screen were negative. CT abdomen and pelvis was negative for pancreatic abnormality. In the absence of evidence for acquired causes of hyperinsulinemic hypoglycemia, congenital cases were investigated. Based on that, further labs were obtained including ammonia levels which was elevated at 177.2 u/dl [15-45]. Accordingly, GLUD-1 gene mutation was sent, given high suspicion for hyperinsulinemic hyperammonemia syndrome, which resulted positive and confirmed the diagnosis. She was started on a protein restricted diet and diazoxide which regulated her blood glucose levels effectively. Discussion Hyperinsulinism/hyperammonemia (HI/HA) syndrome is a form of congenital hyperinsulinism caused by activating mutations of the GLUD 1 gene which encodes Glutamate Dehydrogenase, a key enzyme in the beta cell pathway of amino acid-stimulated insulin secretion. The resultant syndrome is characterized by fasting and protein induced hypoglycemia, elevated serum ammonia levels without typical hyperammonemic symptoms. Management includes effective blood glucose control with an insulin inhibitor such as diazoxide and a protein restricted diet with consideration to predominantly include carbohydrates and fat. Conclusion Hyperinsulinemia hyperammonemia is a rare form of congenital hyperinsulinemia typically diagnosed during infancy and should be considered as a possible differential diagnosis in patients presenting with new onset hypoglycemia, as timely diagnosis and intervention can prevent forthcoming neurological complications. Presentation: No date and time listed

Case Report: A Case of Adult Nesidioblastosis

Background: Adult nesidioblastosis is an extremely rare cause of hyperinsulinaemic hypoglycaemia, however its diagnosis has been on the rise in recent years. It is characterised by beta-cell hypertrophy and diffused islet hyperplasia. In contrast to infantile nesidioblastosis secondary to a genetic defect, the cause of adult nesidioblastosis is largely unknown. Case report: We report a case of hyperinsulinaemic hypoglycaemia in an 83-year-old man with biochemical derangements consistent with a diagnosis of insulinoma. Preoperative cross-sectional imagings, Dotatate PET, and visceral angiogram all failed to definitively localise a neuroendocrine tumour. Selective arterial calcium stimulation showed a subtle increase in insulin secretion from the tail of the pancreas. After an unrevealing intraoperative ultrasound, a distal pancreatectomy was performed with pathology showing diffused islet hyperplasia consistent with a diagnosis of nesidioblastosis. Postoperative euglycaemia was achieved and persisted to the time of manuscript submission four months later. Conclusion: Clinically and biochemically it is extremely difficult to distinguish nesidioblastosis from insulinoma. The sensitivity of different preoperative localising modalities for insulinoma varies with the gold standard being selective arterial calcium stimulation. In contrast to insulinoma, response to selective arterial calcium stimulation could be subtle in nesidioblastosis, and such subtlety should raise the suspicion for the latter especially in the presence of unrevealing imaging findings. Given reports of coexistence of insulinoma and nesidioblastosis along with other known entities such as multifocal insulinoma and focal nesidioblastoma, we postulate pathological beta cell hyperplasias fall on a continuous spectrum of hyperfunctioning beta cell disorders as opposed to the current dichotomous understanding.

An Unusual Cause of Hypoglycemia: Insulin Autoimmune Syndrome

Insulin autoimmune syndrome (IAS) is a rare cause of hyperinsulinemic hypoglycemia characterized by antibodies to endogenous insulin without exposure to exogenous insulin. In this report, we presented a case of insulin autoimmune syndrome with a history of fasting hypoglycemia. After work up and exlusion of other causes such as insulinoma, hyperinsulinemic hypogylcemic state of the patient was considered to have been induced by etofenamate. Although IAS is generally self limiting and dietary management and withdrawal of trigger drug are enough to maintain euglycemia, in some cases corticosteroids, plasmapheresis, rituximab can be used for treatment. In our case, despite dietary management, hypoglycemia was severe and the patient’s life quality was adversely effected. After treatment with prednisolone, hypoglycemic episodes became less and less frequent. IAS should be considered as a differential diagnosis of hyperinsulinemic hypogylcemic states to avoid unnecessary interventions.

Multifocal insulinoma secondary to insulinomatosis: persistent hypoglycaemia despite total pancreatectomy.

SummaryInsulinomatosis is a rare cause of hyperinsulinaemic hypoglycaemia. The ideal management approach is not known. A 40-year-old woman with recurrent symptomatic hyperinsulinaemic hypoglycaemia was diagnosed with an insulinoma. A benign 12 mm pancreatic head insulinoma was resected but hypoglycaemia recurred 7 years later. A benign 10 mm pancreatic head insulinoma was then resected but hypoglycaemia recurred within 2 months. Octreotide injections were trialled but exacerbated hypoglycaemia. After a 2-year interval, she underwent total pancreatectomy. A benign 28 mm pancreatic head insulinoma was found alongside insulin-expressing monohormonal endocrine cell clusters (IMECCs) and islet cell hyperplasia, consistent with a diagnosis of insulinomatosis. Hypoglycaemia recurred within 6 weeks. There was no identifiable lesion on MRI pancreas, Ga-68 PET or FDG PET. Diazoxide and everolimus were not tolerated. MEN-1 testing was negative. Insulinomatosis should be suspected in insulinomas with early recurrence or multifocality. De novo lesions can arise throughout the pancreas. Extensive surgery will assist diagnosis but may not provide cure.Learning points:Insulinomas are usually benign and managed surgically.Insulinomatosis is characterised by multifocal benign insulinomas with a tendency to recur early. It is rare.Multifocal or recurrent insulinomas should raise suspicion of MEN-1 syndrome, or insulinomatosis.Insulinomatosis is distinguished histologically by insulin-expressing monohormonal endocrine cell clusters (IMECCs) and tumour staining only for insulin, whereas MEN-1 associated insulinomas stain for multiple hormones.The ideal treatment strategy is unknown. Total pancreatectomy may not offer cure.

Congenital hyperinsulinism: from molecular genetics to clinical practice

Persistent hypoglycemia in the neonatal period is a serious metabolic disorder that can cause seizures, coma, permanent brain damage and death. The main cause of hyperinsulinemic hypoglycemia in newborns is endogenous transient and congenital hyperinsulinism. Transitory forms can be associated with maternal factors, genetic syndromes and perinatal stress (asphyxia, maternal toxemia, intrauterine growth retardation, prematurity). The most severe forms of persistent hypoglycemia in infants include congenital hyperinsulinism (CHI). Recent progress in genetics has led to understanding of relations between CHI and the mutations in genes that play key roles in insulin secretion regulating. The most common mutations are defects in ATP­dependent potassium channels (KATP channels) genes. KATP channels are the link between intracellular glucose metabolism, membrane potential of islet cells and insulin secretion. They are the target for the drugs for hyperinsulinism treatment. Other monogenic forms of CHI include mutations of genes involved in intracellular glucose metabolism, ATP synthesis regulation and transcription factors. There are two main histological forms of CHI: diffuse and focal. The article presents diagnostic and treatment algorithm for CHI. The first­line drug for the treatment of all types of CHI is diazoxide. It is effective in all forms of CHI with intact KATP channels. Octreotide (a synthetic analog of somatostatin) is a second­line drug for therapy of CHI. The article presents new drugs for the treatment of CHI: sirolimus and glucagon­like peptide­1 antagonists.

Refinement of the critical genomic region for congenital hyperinsulinismin the Chromosome 9p deletion syndrome.

Background: Large contiguous gene deletions at the distal end of the short arm of chromosome 9 result in the complex multi-organ condition chromosome 9p deletion syndrome. A range of clinical features can result from these deletions with the most common being facial dysmorphisms and neurological impairment. Congenital hyperinsulinism is a rarely reported feature of the syndrome with the genetic mechanism for the dysregulated insulin secretion being unknown. Methods: We studied the clinical and genetic characteristics of 12 individuals with chromosome 9p deletions who had a history of neonatal hypoglycaemia. Using off-target reads generated from targeted next-generation sequencing of the genes known to cause hyperinsulinaemic hypoglycaemia (n=9), or microarray analysis (n=3), we mapped the minimal shared deleted region on chromosome 9 in this cohort. Targeted sequencing was performed in three patients to search for a recessive mutation unmasked by the deletion. Results: In 10/12 patients with hypoglycaemia, hyperinsulinism was confirmed biochemically. A range of extra-pancreatic features were also reported in these patients consistent with the diagnosis of the Chromosome 9p deletion syndrome. The minimal deleted region was mapped to 7.2 Mb, encompassing 38 protein-coding genes. In silico analysis of these genes highlighted SMARCA2 and RFX3 as potential candidates for the hypoglycaemia. Targeted sequencing performed on three of the patients did not identify a second disease-causing variant within the minimal deleted region. Conclusions: This study identifies 9p deletions as an important cause of hyperinsulinaemic hypoglycaemia and increases the number of cases reported with 9p deletions and hypoglycaemia to 15 making this a more common feature of the syndrome than previously appreciated. Whilst the precise genetic mechanism of the dysregulated insulin secretion could not be determined in these patients, mapping the deletion breakpoints highlighted potential candidate genes for hypoglycaemia within the deleted region.

Refinement of the critical genomic region for congenital hyperinsulinism in the Chromosome 9p deletion syndrome

Background: Large contiguous gene deletions at the distal end of the short arm of chromosome 9 result in the complex multi-organ condition chromosome 9p deletion syndrome. A range of clinical features can result from these deletions with the most common being facial dysmorphisms and neurological impairment. Congenital hyperinsulinism is a rarely reported feature of the syndrome with the genetic mechanism for the dysregulated insulin secretion being unknown. Methods: We studied the clinical and genetic characteristics of 12 individuals with chromosome 9p deletions who had a history of neonatal hypoglycaemia. Using off-target reads generated from targeted next-generation sequencing of the genes known to cause hyperinsulinaemic hypoglycaemia (n=9), or microarray analysis (n=3), we mapped the minimal shared deleted region on chromosome 9 in this cohort. Targeted sequencing was performed in three patients to search for a recessive mutation unmasked by the deletion. Results: In 10/12 patients with hypoglycaemia, hyperinsulinism was confirmed biochemically. A range of extra-pancreatic features were also reported in these patients consistent with the diagnosis of the Chromosome 9p deletion syndrome. The minimal deleted region was mapped to 7.2 Mb, encompassing 38 protein-coding genes. In silico analysis of these genes highlighted SMARCA2 and RFX3 as potential candidates for the hypoglycaemia. Targeted sequencing performed on three of the patients did not identify a second disease-causing variant within the minimal deleted region. Conclusions: This study identifies 9p deletions as an important cause of hyperinsulinaemic hypoglycaemia and increases the number of cases reported with 9p deletions and hypoglycaemia to 15 making this a more common feature of the syndrome than previously appreciated. Whilst the precise genetic mechanism of the dysregulated insulin secretion could not be determined in these patients, mapping the deletion breakpoints highlighted potential candidate genes for hypoglycaemia within the deleted region.

Hyperinsulinism hyperammonaemia (HI/HA) syndrome due to GLUD1 mutation: phenotypic variations ranging from late presentation to spontaneous resolution.

Background The hyperinsulinism/hyperammonaemia (HI/HA) syndrome is the second most common cause of hyperinsulinaemic hypoglycaemia, caused by activating mutations in GLUD1. In this article, we report a series of three unrelated patients with HI/HA syndrome who demonstrated variable phenotypes, ranging from delayed presentation to spontaneous resolution of hypoglycaemia, thereby expanding the current knowledge and understanding of GLUD1 mutations. Case presentation This paper is a retrospective analysis of patients with HI/HA syndrome who demonstrated a variable disease course. Patient 1 presented with hypoglycaemic seizures at the age of 7 months and was diagnosed with HI/HA syndrome. Patient 2, a 5-year-old boy, on anti-convulsants since 8 months of age, was diagnosed with HI/HA at the age of 4 years. Patient 3, an 11-year-old girl with a history of transient neonatal hypoglycaemia, was diagnosed with HI/HA at the age of 12 months following evaluation for absence seizures. Patients 1 and 2 had raised ammonia levels, whilst patient 3 had normal ammonia level. The genetic analysis in all three patients confirmed GLUD1 mutation. Good glycaemic control was observed in all following diazoxide treatment. All patients have learning difficulties. Patient 1 demonstrated spontaneous resolution of hypoglycaemia at the age of 8 years, enabling discontinuation of diazoxide. Conclusions The cases highlight the diagnostic challenges in HI/HA syndrome due to a highly variable presentation. Knowledge of variable phenotypes would enable early diagnosis, thereby decreasing the risk of long-term neurological damage. Spontaneous resolution of hyperinsulinism could occur, and it is important to consider a trial off diazoxide therapy especially if the patients are on a small dose of diazoxide.

MON-640 Endogenous Insulin and C-Peptide Suppression Test Using a Rapid-Acting Insulin Analog in the Diagnosis of Insulinoma

C-peptide suppression test (CPS) was shown to diagnose the cause of hyperinsulinemic hypoglycemia, i.e. insulinoma, as effectively as supervised 72-hour fast test with less time consuming and cost. In the conventional CPS, regular insulin (RI) is used to induce hypoglycemia that subsequently suppresses endogenous insulin secretion. As RI is measurable in plasma insulin (PI) assay, plasma C-peptide (PCP) but not PI response is therefore used for assessment of endogenous insulin secretion in CPS using RI. As rapid acting insulin analogs (RA) are not measurable in a selected PI assay, both PCP and PI levels can be used to assess endogenous insulin secretion if an RA is used instead of RI in CPS. There is no study on PI and PCP responses to RA in insulinoma. This study aimed to examine efficacy of modified CPS, so-called insulin and C-peptide suppression test (ICPS) by using an RA (insulin aspart) in the diagnosis of insulinoma. Ten patients, 7 with histopathological proven insulinoma (IN) and 3 with non-insulinoma (non-IN), underwent ICPS. Blood samples were collected for measurement of plasma glucose (PG), PCP, and PI using a Roche Cobas 8000 module e602 which does not measure insulin aspart at before and every 10-20 minutes during intravenous infusion of insulin aspart at the rate of 0.05-0.075 unit/kg/hr. The test was terminated if the patients had a PG level of <40 mg/dL. There was no difference in baseline biochemical data between two groups. At the end of the test, IN had significantly higher PCP level (range: 0.60-10.20 vs. 0.31-0.48 ng/mL and median: 4.67 vs. 0.47 ng/mL; p = 0.017), lower percentage of PCP suppression (range: 2.10-53.10% vs. 63.08-91.24% and mean: 24.78 ± 19.4% vs. 73.17 ± 15.7%; p = 0.005), higher PI level (range: 1.13-113.70 vs. 0.22-0.73 µIU/mL and median: 21.29 vs. 0.49 µIU/mL; p = 0.017) and lower percentage of PI suppression (range: -14.63-81.32% vs. 88.14-96.10% and mean: 28.45 ± 36.2% vs. 93.31 ± 4.5%; p = 0.003) than did the non-IN. No overlapping of these parameters was observed between IN and non-IN. Using the same cut-off levels as the supervised 72-hour fast test, the insulin criterion (≥3 µIU/mL) in ICPS had a sensitivity of 86% and a specificity of 100% and the C-peptide criterion (≥0.6 ng/mL) in ICPS had a sensitivity of 100% and a specificity of 100%. There was a high correlation of 89% between using PCP and PI responses. In conclusion, ICPS using an RA is effective in the diagnosis of insulinoma.

MON-070 Cross-Reactivity of Human Insulin and Insulin Analogues in Human Insulin Immunoassay Complicates Case of Medical Child Abuse

Background: Measurement of insulin levels with human insulin immunoassays is important in the investigation of hypoglycemia; however, cross-reactivity with insulin analogues complicates clinical assessment. Clinical Case: A 2-month-old male presented with hypoglycemia. Initial tests were consistent with hyperinsulinemic hypoglycemia: low serum glucose (29 mg/dL, n 70 to 99), elevated insulin (90.1 mU/L, n 3.0 to 19.0), suppressed beta-hydroxybutyrate (0.16 mmol/L, n 0.02 to 0.27), and suppressed free fatty acids (0.27 mmol/L, n 0.50 to 1.60). C-peptide level resulted undetectable (<0.1 ng/mL, n 0.8 to 3.5) raising suspicion for exogenous insulin administration. History revealed an older brother with type 1 diabetes mellitus treated with insulins glargine and lispro. Only one caregiver was present in the hospital, who denied knowledge of exogenous insulin administration. Hypoglycemia persisted despite placement of a continuous 1:1 sitter, high-dose intravenous glucose (glucose infusion rate up to 21.6 mg/kg/min), and treatment with diazoxide. A repeat insulin measurement with the Roche Diagnostics assay specific for human insulin was performed on a critical sample and resulted elevated (13.9 uIU/L, n 2.6 to 24.9), suggestive of endogenous insulin. However, an extensive study of commercial human insulin immunoassays by Heurtault et al., including the Roche Diagnostics assay, has demonstrated cross-reactivity with insulin analogues and their metabolites [1]. Given persistent concern for exogenous insulin administration, the patient’s caregiver was asked to leave the bedside for an extended period of time which resulted in normoglycemia. Diazoxide and dextrose-containing IV fluids were discontinued. Patient maintained normoglycemia for the remainder of the admission and was discharged in the care of child protective services. Conclusions: Cross-reactivity exists in human insulin immunoassays with insulin analogues and their metabolites complicating the determination of endogenous versus exogenous insulin as the cause of hyperinsulinemic hypoglycemia. It is important to know the cross-reactivity of the assay used if a diagnosis of surreptitious insulin administration is suspected. Separation of patient and possible perpetrators and involvement of child protective services is essential in suspected cases of exogenous insulin administration. Evaluation in cases where self-injection of insulin is suspected may be more difficult to decipher, and inclusion of c-peptide measurement at the time of hypoglycemia is critical. Reference: [1] Heurtault B, Reix N, Meyer N, et al. Extensive study of human insulin immunoassays: promises and pitfalls for insulin analogue detection and quantification. Clin Chem Lab Med. 2014; 52:355-362.

Insulin Autoimmune Syndrome (Hirata Disease): A Comprehensive Review Fifty Years After Its First Description.

Insulin autoimmune syndrome (IAS), also named Hirata’s disease, is a rare condition characterized by hypoglycemic episodes due to the presence of high titers of insulin autoantibodies (IAA). IAS is a form of immune-mediated hypoglycemia, which develops when a triggering factor (ie, a medication or a viral infection) acts on an underlying predisposing genetic background. IAS pathogenesis involves the formation of insulin-IAA complexes that induce glycemic alterations with a double-phase mechanism: IAA prevent 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. The diagnosis of IAS is challenging, requiring a careful workup aimed at excluding other causes of hyperinsulinemic hypoglycemia. The gold standard for the definitive diagnosis is the finding of IAA in a blood sample. Because IAS is frequently a self-remitting disease, its management mostly consists of supportive measures, such as dietary modifications, aimed at preventing the development of hypoglycemia. Pharmacological therapies may occasionally be necessary for patients presenting with severe manifestations of IAS. Available therapies may include drugs that reduce pancreatic insulin secretion (somatostatin analogues and diazoxide, for instance) and immunosuppressive agents (glucocorticoids, azathioprine and rituximab). The purpose of this review is to provide a comprehensive analysis of the disease, by describing the burden of knowledge that has been obtained in the 50 years following its first description, took in 1970, and by highlighting the points that are still unclear in its pathogenesis and management.

Successful Medical Treatment of Hyperinsulinemic Hypoglycemia in the Adult: A Case Report and Brief Literature Review

Hyperinsulinemic hypoglycemia is characterized by inappropriate insulin secretion from the pancreatic beta cells causing low blood glucose levels. Nesidioblastosis is a very rare cause of hyperinsulinemic hypoglycemia in adults. Medical therapy can effectively improve disease symptoms. In 2014, a 45-year-old man presented with recurrent severe fasting and postprandial symptomatic hypoglycemia. The symptoms resolved after glucose ingestion. Fasting test was positive after only 4 h but imaging methods (abdominal computerized tomography, magnetic resonance imaging, endoscopic ultrasonography and octreotide scintigraphy) failed to identify pancreatic lesions. Hypoglycemia in face of endogenous hyperinsulinemia and lack of focal lesions in the pancreas in multiple imaging exams suggested the diagnosis of adult nesidioblastosis. The patient preferred conservative medical treatment in association with dietary recommendations. Nifedipine (30 mg/day) did not improve the glycemic profile and was poorly tolerated by the patient. Diazoxide 150 mg/day was started, with progressive increase to 400 mg/day over 6 weeks. Patient has been successfully treated with medical treatment for 5 years, with no events of severe hypoglycemia, no significant side effects and with marked improvement in quality of life. This clinical case demonstrates that adult hyperinsulinemic hypoglycemia can be effectively controlled with medical treatment, which is a viable alternative to pancreatic surgery. J Endocrinol Metab. 2019;9(6):199-202 doi: https://doi.org/10.14740/jem617