Persistent Hypoglycemia Research Articles

P383 THIRD–DEGREE ATRIOVENTRICULAR BLOCK AND HYPERCALCEMIA: NOT ALWAYS JUST THE HEART

Abstract A 81–year–old lady was admitted to the ER due to anorexia, fever and oliguria. Previous medical history was unknown as she had arrived in Italy one month before and her son was not aware of it. Upon arrival she was soporous and bradicardic. Physical examination consisted of mild pulmonary rales, diffuse abdominal pain and leg edema. ECG showed a third–degree atrioventricular block with narrow QRS and average heart rate of 40 bpm with no signs of ischemia. X–ray showed mild congestion. She was admitted to CCU. Blood tests showed hypoglicemia (53 mg/dL), anemia (Hb 9.9g/dL), low platelet count, renal dysfunction (creatinine 1.43mg/dL), high C–reactive protein, normal potassium but high calcemia (13 mg/dL). To investigate hypercalcemia parathyroid hormone was dosed and was in range, so a CT scan was needed to rule out pancreatitis, cancer or bone lesions. Also a cardiac echo was done: it showed a hypertrophic left ventricle with preserved contractility, no significant valvular dysfunctions, normal right sections with pulmonary hypertension, no pericardial effusion. While performing the subcostal view however multiple formations were seen at the hepatic level. CT scan confirmed multiple pathological conglomerating lymphadenopathies in the abdomen towards the femoral region, reaching 5 cm of diameter; no bone lesions were found. Inguinal lymph node biopsy was performed. Due to persistent complete AV block along with persistent hypercalcemia and hypoglycemia despite medical therapy, considering the electrolyte imbalance not corrigible due to a malignancy a pacemaker was implanted. The result of the lymph node biopsy was consistent with a form of Diffuse Large B–Cell Lymphoma. This case highlights how a 3–rd degree AV block may present with non–specific symptoms. When it is found it may not always represent a pure cardiac problem as sometimes it is the epiphenomenon of a systemic disease. Particularity of this case is that cardiologists are less used to take into consideration calcium balance. Nevertheless, although infrequent, hypercalcemia is a cause of significant conduction disease. After having looked for it, searching for its etiology is mandatory as some could be reversible and thus the AV block as well. For this reason, when a complete AV block is found ruling out hypercalcemia is fundamental, taking into consideration that the conduction disease may represent the first red flag of an unknown malignancy

A case of insulinoma confused with dumping syndrome after total gastrectomy

We present the case of a 70-year-old female patient with persistent hypoglycemia after total gastrectomy due to gastrointestinal stromal tumors. She was thought to have late dumping syndrome but was diagnosed with insulinoma after further examination. Dumping syndrome is mainly seen after stomach or esophageal surgery. It is divided into early dumping and late dumping syndrome. Late dumping syndrome is initially manifested by an exaggerated insulin response and reactive hypoglycemia after glucagon-like peptide-1 release. Diagnosis is based on clinical findings. Treatment mainly consists of reducing carbohydrate intake and not ingesting solid and liquid foods together. In cases where diet alone is not sufficient, acarbose, an α-glucosidase inhibitor that slows the digestion of carbohydrates, may be beneficial for late dumping. Octreotide can be used in resistant cases. However, the diagnosis of insulinoma, which leads to a similar clinical presentation in resistant dumping cases, should be kept in mind. Our patient who showed clinical signs of dumping syndrome after gastrectomy, and treatment-resistant hypoglycemia was diagnosed with insulinoma on the basis of further investigations. The patient’s symptoms resolved after surgery for insulinoma.

Abstract #1171127: Recurrent fasting hypoglycemia in a patient with insulin-dependent diabetes and monoclonal gammopathy of undetermined significance

Insulin autoimmune syndrome (IAS) and exogenous insulin autoimmune syndrome (EIAS) are characterized by hypoglycemia, hyperinsulinemia and the presence of insulin antibodies (IAs). This case illustrates the diagnostic dilemma that is faced with regard to distinguishing EIAS from IAS in a diabetic patient on insulin with persistent fasting hypoglycemia who interestingly also had monoclonal gammopathy of undetermined significance (MGUS).

Perioperative management of congenital hyperinsulinism (CHI)

Congenital hyperinsulinism (CHI) is one of the common causes of recurrent or persistent hypoglycemia. It is marked by islet cell dysfunction leading to insufficient suppression of insulin secretion in the presence of serious hypoglycemia. CHI is genetic in origin, where children present with symptoms of hypoglycemia like irritability, listlessness, nausea, vomiting, tachypnoea, seizure or with long-term sequelae such as developmental delay and focal neurologic deficits, thus making it a medical emergency. Surgical management becomes essential in most of the cases with challenging perioperative management. We successfully managed three such cases with favorable postoperative outcome.

Generation of the human induced pluripotent stem cell line (IBKMOLi002-A) from PBMCs of a patient carrying the heterozygous L271H mutation of the voltage-gated calcium channel subunit Cav1.3-encoding CACNA1D gene

Congenital hyperinsulinemic hypoglycemia (HH) is the most frequent cause of persistent and recurrent hypoglycemia. Peripheral mononuclear blood cells (PBMCs) from a patient diagnosed with HH, alongside autism-spectrum-disorder (ASD), carrying a heterozygous c.812 T>A (L271H) mutation in the voltage-gated calcium channel subunit Cav1.3-encoding gene CACNA1D, were reprogrammed into induced pluripotent stem cells (iPSC). The CACNA1D L271H iPSC (IBKMOLi002-A) exhibit a normal karyotype, high expression of pluripotency-associated markers and the capacity to differentiate into cells of all three germ layers. We provide a novel patient-specific iPSC line, allowing to study HH, ASD, the associated neurodevelopmental disorder as well as CACNA1D-associated channelopathies in general.

Carbamazepine promotes surface expression of mutant Kir6.2-A28V ATP-sensitive potassium channels by modulating Golgi retention and autophagy

Pancreatic β-cells express ATP-sensitive potassium (KATP) channels, consisting of octamer complexes containing four sulfonylurea receptor 1 (SUR1) and four Kir6.2 subunits. Loss of KATP channel function causes persistent hyperinsulinemic hypoglycemia of infancy (PHHI), a rare but debilitating condition if not treated. We previously showed that the sodium-channel blocker carbamazepine (Carb) corrects KATP channel surface expression defects induced by PHHI-causing mutations in SUR1. In this study, we show that Carb treatment can also ameliorate the trafficking deficits associated with a recently discovered PHHI-causing mutation in Kir6.2 (Kir6.2-A28V). In human embryonic kidney 293 or INS-1 cells expressing this mutant KATP channel (SUR1 and Kir6.2-A28V), biotinylation and immunostaining assays revealed that Carb can increase surface expression of the mutant KATP channels. We further examined the subcellular distributions of mutant KATP channels before and after Carb treatment; without Carb treatment, we found that mutant KATP channels were aberrantly accumulated in the Golgi apparatus. However, after Carb treatment, coimmunoprecipitation of mutant KATP channels and Golgi marker GM130 was diminished, and KATP staining was also reduced in lysosomes. Intriguingly, Carb treatment also simultaneously increased autophagic flux and p62 accumulation, suggesting that autophagy-dependent degradation of the mutant channel was not only stimulated but also interrupted. In summary, our data suggest that surface expression of Kir6.2-A28V KATP channels is rescued by Carb treatment via promotion of mutant KATP channel exit from the Golgi apparatus and reduction of autophagy-mediated protein degradation.

Persistent hypoglycemia in the setting of metastatic malignant insulinoma to the liver treated with chemoembolization and bland embolization

Persistent hypoglycemia in the setting of metastatic malignant insulinoma to the liver treated with chemoembolization and bland embolization

Persistent hypoglycemia in the setting of metastatic malignant insulinoma to the liver treated with chemoembolization and bland embolization

We are describing a patient with malignant insulinoma and unusual clinical and pathological features. The patient presented late in the course of the disease with history of abdominal pain and was found to have large tumor of the pancreas and metastasis to the liver. Also, he presented with acute diarrhea which is not a feature of Insulinoma. During the hospital stay the patient had sever hypoglycemia with very inappropriately high to the low blood glucose levels of Insulin, C- peptide and Proinsulin. On biopsy of the tumor it was found to be neuroendocrine tumor, but staining’s for Insulin were negative. The patient was treated with surgical resection of the distal pancreas when the insulinoma was located, splenectomy, cholecystectomy and appendectomy. Also, chemoembolization and embolization of the metastatic tumors of the liver were done and patient’s hypoglycemia was treated with Diazoxide and short course of Steroids and Octreotide. We underscore the need of combined clinical, laboratory, radiological and pathological approach while diagnosing malignant Insulinoma.

Diazoxide-Associated Pulmonary Hypertension in Patient with Hyperinsulinemic Hypoglycemia

Background: Congenital hyperinsulinism (CHI) is the most common of persistent hypoglycemia in infancy characterized by inappropriate insulin secretion in the presence of hypoglycemia. Objective: This case report evaluates the effect of Diazoxide treatmentin inducing pulmonary hypertension in a patient with hyperinsulinemic hypoglycemia. Case findings: A full-term baby male, birth weight 4.3kg, was born at 41 weeks gestation by emergency caesarean section due to fetal distress born in Al-Dawadmi Hospital. He developed convulsions started postnatally loaded with phenobarbitone then shifted to AL-Yamammah hospital as lifesaving case to be admitted in Neonatal ICU. He was found to have hyperinsulinemic hypoglycemia and started on Diazoxide. The patient readmitted in Pediatric ICUat age of 2 month with hypoxic respiratory failure. After evidence of pulmonary hypertension by Echocardiography, Diazoxide was held at 2nd day of admission but he developed recurrent attacks of hypoglycemia required Octreotide with intermittent glucagon. After 14 days, Echocardiographic study repeated and showed findings of non-obstructive hypertrophic cardiomyopathy with good systolic function and no evidences of pulmonary hypertension (PH). Conclusions: Pulmonary hypertension may be developed during Diazoxide therapy. Pulmonaryhypertension was evaluated by echocardiography at regular intervals. This complicationresolved once diazoxide has been withdrawn.

Placental nutrient transporters adapt during persistent maternal hypoglycaemia in rats

Maternal malnutrition is associated with decreased nutrient transfer to the foetus, which may lead to foetal growth restriction, predisposing children to a variety of diseases. However, regulation of placental nutrient transfer during decreased nutrient availability is not fully understood. In the present study, the aim was to investigate changes in levels of placental nutrient transporters accompanying maternal hypoglycaemia following different durations and stages of gestation in rats. Maternal hypoglycaemia was induced by insulin-infusion throughout gestation until gestation day (GD)20 or until end of organogenesis (GD17), with sacrifice on GD17 or GD20. Protein levels of placental glucose transporters GLUT1 (45/55 kDa isotypes) and GLUT3, amino acid transporters SNAT1 and SNAT2, and insulin receptor (InsR) were assessed. On GD17, GLUT1-45, GLUT3, and SNAT1 levels were increased and InsR levels decreased versus controls. On GD20, following hypoglycaemia throughout gestation, GLUT3 levels were increased, GLUT1-55 showed the same trend. After cessation of hypoglycaemia at end of organogenesis, GLUT1-55, GLUT3, and InsR levels were increased versus controls, whereas SNAT1 levels were decreased. The increases in levels of placental nutrient transporters seen during maternal hypoglycaemia and hyperinsulinemia likely reflect an adaptive response to optimise foetal nutrient supply and development during limited availability of glucose.

Hyperinsulinism

Congenital or monogenic hyperinsulinism (HI) is a group of rare genetic disorders characterized by dysregulated insulin secretion and is the most common cause of persistent hypoglycemia in children. Knowledge of normal glucose homeostasis allows for a better understanding of the underlying pathophysiology of hyperinsulinemic hypoglycemia, facilitating timely diagnosis and management. The goal of management is to prevent cerebral insults secondary to hypoglycemia, which can result in poor neurologic outcomes and intellectual disability. Responsiveness to diazoxide, the first-line pharmacologic therapy for persistent hypoglycemia, is also the first step to distinguishing the different genotypic causes of monogenic hyperinsulinism. Early genetic testing becomes necessary when monogenic HI is strongly considered. Knowledge of specific gene mutations allows the determination of a clinical prognosis and definite therapeutic options, such as identifying those with focal forms of hyperinsulinism, who may attain a complete cure through surgical removal of specific affected parts of the pancreas. However, the lack of identifiable cause in a considerable number of patients identified with HI suggests there may be other genetic loci that are yet to be discovered. Furthermore, continued research is needed to explore new forms of therapy, particularly in severe, diazoxide-nonresponsive cases.

Variation in Glycemic Outcomes in Focal Forms of Congenital Hyperinsulinism-The UK Perspective.

ContextIn focal congenital hyperinsulinism (CHI), localized clonal expansion of pancreatic β-cells causes excess insulin secretion and severe hypoglycemia. Surgery is curative, but not all lesions are amenable to surgery.ObjectiveWe describe surgical and nonsurgical outcomes of focal CHI in a national cohort.MethodsPatients with focal CHI were retrospectively reviewed at 2 specialist centers, 2003-2018.ResultsOf 59 patients with focal CHI, 57 had heterozygous mutations in ABCC8/KCNJ11 (51 paternally inherited, 6 de novo). Fluorine-18 L-3,4 dihydroxyphenylalanine positron emission tomography computed tomography scan identified focal lesions in 51 patients. In 5 patients, imaging was inconclusive; the diagnosis was established by frozen section histopathology in 3 patients, a lesion was not identified in 1 patient, and 1 declined surgery. Most patients (n = 56) were unresponsive to diazoxide, of whom 33 were unresponsive or partially responsive to somatostatin receptor analog (SSRA) therapy. Fifty-five patients underwent surgery: 40 had immediate resolution of CHI, 10 had persistent hypoglycemia and a focus was not identified on biopsy in 5. In the 10 patients with persistent hypoglycemia, 7 underwent further surgery with resolution in 4 and ongoing hypoglycemia requiring SSRA in 3. Nine (15% of cohort) patients (1 complex surgical access; 4 biopsy negative; 4 declined surgery) were managed conservatively; medication was discontinued in 8 children at a median (range) age 2.4 (1.5-7.7) years and 1 remains on SSRA at 16 years with improved fasting tolerance and reduction in SSRA dose.ConclusionDespite a unifying genetic basis of disease, we report inherent heterogeneity in focal CHI patients impacting outcomes of both surgical and medical management.

Hyperinsulinemic hypoglycemia in adolescents: case report and systematic review

BackgroundHyperinsulinemic hypoglycemia is the most common cause of severe and persistent hypoglycemia in neonates and children. It is a heterogeneous condition with dysregulated insulin secretion, which persists in the presence of low blood glucose levels.Case presentationWe report a case of a 15 year-old male with hyperinsulinemic hypoglycemia, who underwent a subtotal pancreatectomy after inadequate response to medical therapy. Pathological examination was positive for nesidioblastosis (diffuse β-cell hyperplasia by H-E and immunohistochemical techniques). The patient’s blood glucose levels normalized after surgery and he remains asymptomatic after 1 year of follow-up. The systematic review allowed us to identify 41 adolescents from a total of 205 cases reported in 22 manuscripts, from a total of 454 found in the original search done in PubMed and Lilacs.ConclusionsAlthough very well reported in children, hyperinsulinemic hypoglycemia can occur in adolescents or young adults, as it happens in our reported case. These patients can be seen, treated and reported by pediatricians or adult teams either way due to the wide age range used to define adolescence. Most of them do not respond to medical treatment, and subtotal distal pancreatectomy has become the elected procedure with excellent long-term response in the vast majority.

Persistent Postgastrectomy Hypoglycemia Unawareness in Patients With Gastric Cancer Unveiled by a Prospective Study.

Late dumping syndrome is a common postgastrectomy complication characterized by reactive hypoglycemia. This study aimed to explore the glycemic trend in patients who underwent gastrectomy for gastric cancer and clarify its changes over time in association with postgastrectomy symptoms. Changes over time in glycemic trend in association with postgastrectomy symptoms have not been evaluated. We conducted a prospective study of 71 patients who underwent curative gastrectomy for gastric cancer between November 2017 and April 2020. The patients underwent continuous glucose monitoring twice-at 1- and 12-month postgastrectomy-and were assessed using the Post-Gastrectomy Syndrome Assessment Scale 37-item questionnaire (PGSAS-37) at 1-, 6-, and 12-month postgastrectomy. Our results revealed that hypoglycemia (<70 mg/dL), especially nocturnal hypoglycemia (00:00-06:00), frequently occurred even at 12-month postgastrectomy. Hypoglycemia improved in total gastrectomy patients but remained unchanged in distal gastrectomy patients, which was still high in both groups at 12-month postgastrectomy. Glycemic variability (SD of the glycemic trend) was exacerbated in both gastrectomy groups. However, the PGSAS-37 symptom scores remained unchanged, and the living status and quality of life tended to improve. Hypoglycemia unawareness, including postprandial hypoglycemia without symptoms and nocturnal hypoglycemia, was evident even 12-month postgastrectomy. Persistent postgastrectomy hypoglycemia unawareness, including late dumping syndrome without symptoms and nocturnal hypoglycemia, should be recognized as an important issue in postgastrectomy syndrome. Therefore, meticulous long-term evaluation for glycemic trends and care of patients is required.

Case of Insulinoma in a 2-Months-Old Infant

INTRODUCTION: Insulinoma is congenital hyperinsulinism of infancy (CHI). It is a type of functional neuroendocrine tumor (NET) in the pancreas that manifests with persistent hypoglycemia caused by inappropriately high secretion of insulin (hyperinsulinemia). Comprehensive and multidisciplinary management is required for a better outcome. CASE PRESENTATION: A 2-months-old girl came to the Emergency unit Sanglah Hospital, with a chief complaint of seizure. The patient had a low blood glucose level, high fasting insulin, high LDH, computed tomography of the abdomen result showed isodense heterogeneous lesions border in the cauda pancreas with size 1.32 × 1.24 × 1.35 cm. The anatomy-pathological result showed pancreatic neuroendocrine tumor WHO Grade II, functional, consistent, and clinically to insulinoma on the tail of the pancreas. The patient was treated with hydrocortisone, nifedipine, and octreotide. The patient underwent laparotomy partial pancreatectomy. In post-surgery condition, she had good drink tolerance, no episode of recurrent seizure, and blood glucose was controlled. CONCLUSION: Insulinoma is a rare disease. The diagnosis was challenging. This case report presents the diagnostic work-up and management of a patient with a persistent hypoglycemia condition that was diagnosed as insulinoma.

Insulinoma in an adolescent female with weight loss: a case report and literature review on pediatric insulinomas.

SummaryInsulinomas are a rare cause of persistent hypoglycemia in a previously healthy child. In addition to symptoms of hypoglycemia, individuals with insulinomas usually present with a history of incessant caloric intake and weight gain due to a constant need to counter hypoglycemia. In addition to an extensive review of the literature, we report the first case of an insulinoma coexisting with reduced appetite secondary to anorexia nervosa in an adolescent female.Learning pointsEliciting a detailed family history is important in hypoglycemia cases.Obtaining a thorough dietary intake, weight history, and menstrual cycles (in females) and considering a psychiatric consultation for an eating disorder when indicated.Although rare in the pediatric population, multiple endocrine neoplasia type 1 syndrome should be considered in the evaluation of children and adolescents with hypoglycemia who also have a family history of pituitary, pancreatic, and/or parathyroid endocrinopathies.

A Case of Persistent Hypoglycemia with Disorder of Sex Development

A Case of Persistent Hypoglycemia with Disorder of Sex Development

F-18 DOPA PET/CT in pediatric patients with hyperinsulinemic hypoglycemia: A correlation with genetic analysis.

Persistent hyperinsulinemic hypoglycemia is a rare but life-threatening disease of infancy and childhood. 18F-DOPA PET/CT has been shown to be a useful modality in the localization of focal pancreatic lesions in these patients. We aimed to assess the role of 18F-DOPA PET/CT in such patients at our institution. In this prospective study, 18F-DOPA PET/CT scans and clinical details of 20 children with clinical diagnosis of hyperinsulinemic hypoglycemia were reviewed. Scans were acquired at 5 min postinjection of 2-3 mCi of 18F-DOPA on dedicated PET/CT scanners (Biograph mCT, Siemens Inc and Discovery PET/CT, GE). Abdominal spot images over 1-2 bed positions were acquired. Additionally, genetic mutation status, where available, was correlated to the scan findings. Out of 20 children (7 female and 13 male), 13 were infants. The age of the children ranged from 3 months to 8 years. Fifteen children had undergone gene analysis, 12 were positive for mutation in ABCC8, 1 for GLUD-1, 1 for GCK mutations and 1 had not shown any mutation. 18F-DOPA PET/CT scan showed 5 focal pancreatic lesions in 5 children (1 in each), two focal lesions in 1 child and diffuse pancreatic uptake in 14 children. 18F-DOPA PET/CT is a useful modality for localizing focal pancreatic lesions in children with persistent hyperinsulinemic hypoglycemia. The detection rate is significantly higher in patients with ABCC8 paternal monoallelic recessive gene mutation. 18F-DOPA PET/CT scan consequent to findings on genetic analysis appears to be useful in planning the management of children with hyperinsulinism.

Expert consensus on standard clinical management of neonatal hypoglycemia in China (2021).

There are many high-risk factors for neonatal hypoglycemia, and persistent severe hypoglycemia can lead to irreversible neurological damage and bring a great burden to family and society. Early standardized prevention and clinical management can effectively reduce the incidence rate of neonatal hypoglycemia and brain injury induced by hypoglycemia; however at present, there is still a lack of unified clinical management guidelines for neonatal hypoglycemia in China, and different medical institutions follow different clinical guidelines developed by other countries for the management of neonatal hypoglycemia. In order to further standardize the clinical management of neonatal hypoglycemia, this consensus is developed by the Group of Neonatology, Pediatric Society, Chinese Medical Association. This consensus provides 21 recommendations to address related clinical issues in the prevention, monitoring, and management of hypoglycemia in neonates with a gestational age of ≥35 weeks.

A young man presenting with persistent hypoglycaemia and reduced level of consciousness: case study with review of literature.

A young man presenting with persistent hypoglycaemia and reduced level of consciousness: case study with review of literature.