scholarly journals Multifocal insulinoma secondary to insulinomatosis: persistent hypoglycaemia despite total pancreatectomy

2020 ◽  
Vol 2020 ◽  
Author(s):  
Jennifer R Snaith ◽  
Duncan McLeod ◽  
Arthur Richardson ◽  
David Chipps
Keyword(s):  
Endocrine Cell ◽  
De Novo ◽  
Total Pancreatectomy ◽  
Pancreatic Head ◽  
Management Approach ◽  
List Type ◽  
Hyperinsulinaemic Hypoglycaemia ◽  
Cell Clusters ◽  
Men 1 ◽  
The Ideal

Summary Insulinomatosis 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.

scholarly journals Partial diazoxide responsiveness in a neonate with hyperinsulinism due to homozygous ABCC8 mutation

2019 ◽  
Vol 2019 ◽  
Author(s):  
Sarah Kiff ◽  
Carolyn Babb ◽  
Maria Guemes ◽  
Antonia Dastamani ◽  
Clare Gilbert ◽  
...  
Keyword(s):  
Total Pancreatectomy ◽  
Significant Risk ◽  
Somatostatin Analogue ◽  
List Type ◽  
Hyperinsulinaemic Hypoglycaemia ◽  
Elevated Glucose ◽  
Diffuse Form ◽  
Term Baby ◽  
Learning Points ◽  
Analogue Octreotide

Summary We report a case of partial diazoxide responsiveness in a child with severe congenital hyperinsulinaemic hypoglycaemia (CHI) due to a homozygous ABCC8 mutation. A term baby, with birth weight 3.8 kg, born to consanguineous parents presented on day 1 of life with hypoglycaemia. Hypoglycaemia screen confirmed CHI. Diazoxide was commenced on day 7 due to ongoing elevated glucose requirements (15 mg/kg/min), but despite escalation to a maximum dose (15 mg/kg/day), intravenous (i.v.) glucose requirement remained high (13 mg/kg/min). Genetic testing demonstrated a homozygous ABCC8 splicing mutation (c.2041-1G>C), consistent with a diffuse form of CHI. Diazoxide treatment was therefore stopped and subcutaneous (s.c.) octreotide infusion commenced. Despite this, s.c. glucagon and i.v. glucose were required to prevent hypoglycaemia. A trial of sirolimus and near-total pancreatectomy were considered, however due to the significant morbidity potentially associated with these, a further trial of diazoxide was commenced at 1.5 months of age. At a dose of 10 mg/kg/day of diazoxide and 40 µg/kg/day of octreotide, both i.v. glucose and s.c. glucagon were stopped as normoglycaemia was achieved. CHI due to homozygous ABCC8 mutation poses management difficulties if the somatostatin analogue octreotide is insufficient to prevent hypoglycaemia. Diazoxide unresponsiveness is often thought to be a hallmark of recessively inherited ABCC8 mutations. This patient was initially thought to be non-responsive, but this case highlights that a further trial of diazoxide is warranted, where other available treatments are associated with significant risk of morbidity. Learning points: Homozygous ABCC8 mutations are commonly thought to cause diazoxide non-responsive hyperinsulinaemic hypoglycaemia. This case highlights that partial diazoxide responsiveness in homozygous ABCC8 mutations may be present. Trial of diazoxide treatment in combination with octreotide is warranted prior to considering alternative treatments, such as sirolimus or near-total pancreatectomy, which are associated with more significant side effects.

scholarly journals Whole-exome sequencing with targeted analysis and epilepsy after acute symptomatic neonatal seizures

2021 ◽  
Author(s):  
Adam L. Numis ◽  
Gilberto da Gente ◽  
Elliott H. Sherr ◽  
Hannah C. Glass
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
List Type ◽  
Sequencing Analysis ◽  
Neonatal Seizures ◽  
Pathogenic Variants ◽  
Targeted Analysis ◽  
Whole Exome ◽  
Epilepsy Gene

Abstract Background The contribution of pathogenic gene variants with development of epilepsy after acute symptomatic neonatal seizures is not known. Methods Case–control study of 20 trios in children with a history of acute symptomatic neonatal seizures: 10 with and 10 without post-neonatal epilepsy. We performed whole-exome sequencing (WES) and identified pathogenic de novo, transmitted, and non-transmitted variants from established and candidate epilepsy association genes and correlated prevalence of these variants with epilepsy outcomes. We performed a sensitivity analysis with genes associated with coronary artery disease (CAD). We analyzed variants throughout the exome to evaluate for differential enrichment of functional properties using exploratory KEGG searches. Results Querying 200 established and candidate epilepsy genes, pathogenic variants were identified in 5 children with post-neonatal epilepsy yet in only 1 child without subsequent epilepsy. There was no difference in the number of trios with non-transmitted pathogenic variants in epilepsy or CAD genes. An exploratory KEGG analysis demonstrated a relative enrichment in cell death pathways in children without subsequent epilepsy. Conclusions In this pilot study, children with epilepsy after acute symptomatic neonatal seizures had a higher prevalence of coding variants with a targeted epilepsy gene sequencing analysis compared to those patients without subsequent epilepsy. Impact We performed whole-exome sequencing (WES) in 20 trios, including 10 children with epilepsy and 10 without epilepsy, both after acute symptomatic neonatal seizures. Children with post-neonatal epilepsy had a higher burden of pathogenic variants in epilepsy-associated genes compared to those without post-neonatal epilepsy. Future studies evaluating this association may lead to a better understanding of the risk of epilepsy after acute symptomatic neonatal seizures and elucidate molecular pathways that are dysregulated after brain injury and implicated in epileptogenesis.

scholarly journals Spontaneously remitting insulin autoimmune syndrome in a patient taking alpha-lipoic acid

2018 ◽  
Vol 2018 ◽  
Author(s):  
D Cappellani ◽  
C Sardella ◽  
M C Campopiano ◽  
A Falorni ◽  
P Marchetti ◽  
...  
Keyword(s):  
Differential Diagnosis ◽  
Lipoic Acid ◽  
University Hospital ◽  
Hypoglycaemic Episode ◽  
List Type ◽  
Alpha Lipoic Acid ◽  
Previous Exposure ◽  
Hyperinsulinaemic Hypoglycaemia ◽  
Insulin Autoimmune Syndrome ◽  
Autoimmune Syndrome

Summary Insulin autoimmune syndrome (IAS), or Hirata disease, is a rare hypoglycaemic disorder caused by the presence of high titer of insulin autoantibodies (IAA) in patients without previous exposure to exogenous insulin. Even though its pathogenesis is not fully understood, striking evidences link IAS to previous exposure to sulphydryl-containing medications, like alpha-lipoic acid, a widely used nutritional supplement. Although challenging, a careful differential diagnosis from other causes of hyperinsulinaemic hypoglycaemia (such as insulinoma) is mandatory, since these conditions require different therapeutic approaches. In the present study, we report a 35-year-old woman originally from Sri Lanka who was referred to our University Hospital on suspicion of occult insulinoma. Her medical history was positive for endometriosis, treated with estroprogestins and alpha-lipoic acid. The latter supplement was begun 2 weeks before the first hypoglycaemic episode. Our tests confirmed the presence of hypoglycaemia associated with high insulin and C-peptide concentrations. When insulin concentrations were compared using different assays, the results were significantly different. Moreover, insulin values significantly decreased after precipitation with polyethylene glycol. An assay for IAA proved positive (530 U/mL). A genetic analysis revealed the presence of HLA-DRB1*04,15, an immunogenetic determinant associated with IAS. On the basis of clinical data we avoided a first-line approach with immunosuppressive treatments, and the patient was advised to modify her diet, with the introduction of frequent low-caloric meals. During follow-up evaluations, glucose levels (registered trough a flash glucose monitoring system) resulted progressively more stable. IAA titer progressively decreased, being undetectable by the fifteenth month, thus indicating the remission of the IAS. Learning points: Insulin autoimmune syndrome (IAS) is a rare cause of hyperinsulinaemic hypoglycaemia, whose prevalence is higher in East Asian populations due to the higher prevalence of specific immunogenetic determinants. Nevertheless, an increasing number of IAS cases is being reported worldwide, due to the wide diffusion of medications such as alpha-lipoic acid. Differential diagnosis of IAS from other causes of hyperinsulinemic hypoglycaemia is challenging. Even though many tests can be suggestive of IAS, the gold standard remains the detection of IAAs, despite that dedicated commercial kits are not widely available. The therapeutic approach to IAS is problematic. As a matter of fact IAS is often a self-remitting disease, but sometimes needs aggressive immunosuppression. The benefits and risks of any therapeutic choice should be carefully weighted and tailored on the single patient.

scholarly journals Autoimmune hypoglycaemia caused by alpha-lipoic acid: a rare condition in Caucasian patients

2018 ◽  
Vol 2018 ◽  
Author(s):  
A Veltroni ◽  
G Zambon ◽  
S Cingarlini ◽  
M V Davì
Keyword(s):  
Lipoic Acid ◽  
Serum Insulin ◽  
Strong Association ◽  
High Serum ◽  
List Type ◽  
Alpha Lipoic Acid ◽  
Hyperinsulinaemic Hypoglycaemia ◽  
C Peptide ◽  
Sulphydryl Groups ◽  
Caucasian Patients

Summary Insulin autoimmune syndrome (IAS), a rare cause of autoimmune hyperinsulinaemic hypoglycaemia, is relatively well known in Japan. The incidence in Caucasians is less than one-fifth of that reported in Japanese people, but it is becoming increasingly recognised worldwide in non-Asians as well. Drugs containing sulphydryl groups are known to be associated with the disease in genetically predisposed individuals. Moreover, several recent reports showed a direct association between the onset of IAS and the consumption of dietary supplements containing alpha-lipoic acid (LA). Insulinoma remains the most prevalent cause of hypersulinaemic hypoglycaemia in Caucasians. Consequently, primary investigation in these patients is generally focused on localisation of the pancreatic tumour, often with invasive procedures followed by surgery. We described a case of an Italian woman presenting to us with severe recurrent hypoglycaemia associated with high insulin and C-peptide levels and no evidence of pancreatic lesions at imaging diagnostic procedures. She had taken LA until 2 weeks before hospitalisation. After an evaluation of her drug history, an autoimmune form of hypoglycaemia was suspected and the titre of insulin autoantibodies was found to be markedly elevated. This allowed us to diagnose LA-related IAS, thus preventing any unnecessary surgery and avoiding invasive diagnostic interventions. Learning points: IAS is a rare cause of hyperinsulinaemic hypoglycaemia that typically affects Asian population, but it has been increasingly recognised in Caucasian patients. It should be considered among the differential diagnosis of hyperinsulinaemic hypoglycaemia to avoid unnecessary diagnostic investigations and surgery. It should be suspected in the presence of very high serum insulin levels (100–10  000  μU/mL) associated with high C-peptide levels. There is a strong association with administration of drugs containing sulphydryl groups included LA, a dietary supplement commonly used in Western countries to treat peripheral neuropathy.

scholarly journals Impact of a novel 14 bp MEN1 deletion in a patient with hyperparathyroidism and gastrinoma

2015 ◽  
Vol 2015 ◽  
Author(s):  
Shweta Birla ◽  
Viveka P Jyotsna ◽  
Rajiv Singla ◽  
Madhavi Tripathi ◽  
Arundhati Sharma
Keyword(s):  
Epigastric Pain ◽  
Novel Mutation ◽  
Mutation Screening ◽  
Deletion Mutation ◽  
Pancreatic Tumors ◽  
List Type ◽  
Men1 Syndrome ◽  
First Degree Relatives ◽  
Men 1 ◽  
Endocrine Organs

Summary Multiple endocrine neoplasia type 1 (MEN-1) is a rare autosomal-dominant disease characterized by tumors in endocrine and/or non endocrine organs due to mutations in MEN1 encoding a nuclear scaffold protein‘menin’ involved in regulation of different cellular activities. We report a novel 14 bp MEN1 deletion mutation in a 35-year-old female with history of recurrent epigastric pain, vomiting, loose stools and weight loss. On evaluation she was diagnosed to have multifocal gastro-duodenal gastrinoma with paraduodenal lymph nodes and solitary liver metastasis. She was also found to have primary hyperparathyroidism with bilateral inferior parathyroid adenoma. Pancreatico-duodenectomy with truncalvagotomy was performed. Four months later, radiofrequency ablation (RFA) of segment 4 of the liver was done followed by three and a half parathyroidectomy. MEN1 screening was carried out for the patient and her family members. MEN-1 sequencing in the patient revealed a heterozygous 14 bp exon 8 deletion. Evaluation for pathogenicity and protein structure prediction showed that the mutation led to a frameshift thereby causing premature termination resulting in a truncated protein. To conclude, a novel pathogenic MEN1 deletion mutation affecting its function was identified in a patient with hyperparathyroidism and gastrinoma. The report highlights the clinical consequences of the novel mutation and its impact on the structure and function of the protein. It also provides evidence for co-existence of pancreatic and duodenal gastrinomas in MEN1 syndrome. MEN1 testing provides important clues regarding etiology and therefore should be essentially undertaken in asymptomatic first degree relatives who could be potential carriers of the disease. Learning points Identification of a novel pathogenic MEN1 deletion mutation. MEN1 mutation screening in patients with pituitary, parathyroid and pancreatic tumors, and their first degree relatives gives important clues about the etiology. Pancreatic and duodenal gastrinomas may co-exist simultaneously in MEN1 syndrome.

scholarly journals U.S. National Debt- A Risk Management Approach

2019 ◽  
Vol 3 (1) ◽  
pp. 28-37
Author(s):  
Simin Hojat ◽  
Denise Ginzo
Keyword(s):  
Risk Management ◽  
Social Impact ◽  
Nobel Laureate ◽  
Management Approach ◽  
National Debt ◽  
Management Tools ◽  
The Social ◽  
The U.S ◽  
Research Show ◽  
The Ideal

The U.S. national debt reached the astounding figure of 22 trillion dollars in 2018 (Gomes & Sinclair, 2019). It splashed onto the headlines of newspapers and became a topic of interest for Nobel laureate economists, dividing opinions on the potential impacts and the necessity of corrective measures. Krugman (2019) advocates that the national debt is trivial for a large economy like the U.S.; whereas, economists, such as Summers (2019), assume a more cautious position in recommending clear restrictions on the never-ending rise in the national debt. Some intriguing questions persist: should measures to restrain or reduce the debt be taken? If so, what is the ideal time to put them into effect? The purpose of this study is to analyze the reasons for the increasing U.S. national debt and to raise a discussion on the ideas of these reputed economists to address these questions. Additionally, the fundamental principles of risk management have been explained to evaluate the national debt from a different perspective (Homan, 2013). The findings of this research show that there are similarities between the theory of risk management and the risk concerns involved in the U.S. national debt. The social impact of this research includes the potential for the risk management tools identified to be used in analyzing the sovereign national debt.

scholarly journals Could total pancreatectomy improve overall survival of pancreatic head adenocarcinoma patients? Preliminary results of prospective study with 110 cases

HPB ◽  
2020 ◽  
Vol 22 ◽  
pp. S374-S375
Author(s):  
F. Sánchez-Bueno ◽  
PJ Gil Vazquez ◽  
J. De la Peña ◽  
E. Ortiz ◽  
R Garcia Perez ◽  
...  
Keyword(s):  
Overall Survival ◽  
Prospective Study ◽  
Total Pancreatectomy ◽  
Pancreatic Head ◽  
Preliminary Results

Efficacy and safety of sirolimus in a neonate with persistent hypoglycaemia following near-total pancreatectomy for hyperinsulinaemic hypoglycaemia

2015 ◽  
Vol 28 (11-12) ◽  
Author(s):  
Mary B. Abraham ◽  
Vinutha B. Shetty ◽  
Glynis Price ◽  
Nicholas Smith ◽  
Martin de Bock ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Total Pancreatectomy ◽  
Efficacy And Safety ◽  
Neonatal Hypoglycaemia ◽  
Hyperinsulinaemic Hypoglycaemia ◽  
Common Cause

AbstractHyperinsulinaemic hypoglycaemia (HH) is characterised by inappropriate insulin secretion and is the most common cause for persistent neonatal hypoglycaemia. The only treatment available for medically unresponsive hypoglycaemia is a near-total pancreatectomy. A neonate with severe HH, due to a homozygous

scholarly journals Paternally inherited ABCC8 mutation causing diffuse congenital hyperinsulinism

2013 ◽  
Vol 2013 ◽  
Author(s):  
Suresh Chandran ◽  
Fabian Yap Kok Peng ◽  
Victor Samuel Rajadurai ◽  
Yap Te Lu ◽  
Kenneth T E Chang ◽  
...  
Keyword(s):  
Ct Scan ◽  
Severe Hypoglycaemia ◽  
Congenital Hyperinsulinism ◽  
List Type ◽  
Focal Lesions ◽  
Hyperinsulinaemic Hypoglycaemia ◽  
Partial Pancreatectomy ◽  
Diffuse Disease ◽  
Pet Ct ◽  
Pet Ct Scan

Summary background: Congenital hyperinsulinism (CHI) is a rare genetic disorder characterised by inappropriate insulin secretion in the face of severe hypoglycaemia. There are two histological subtypes of CHI namely diffuse and focal. Diffuse CHI is most common due to recessive mutations in ABCC8/KCNJ11 (which encode the SUR/KIR6.2 components of the pancreatic β-cell KATP channel) whereas focal CHI is due to a paternally inherited ABCC8/KCNJ11 mutation and somatic loss of heterozygosity for the 11p allele inside the focal lesion. Fluorine-18-l-dihydroxyphenylalanine positron emission tomography/computed tomography (18F-DOPA-PET/CT) is used in the pre-operative localisation of focal lesions prior to surgery. Diffuse CHI if medically unresponsive will require a near total pancreatectomy whereas focal CHI will only require a limited lesionectomy, thus curing the patient from the hypoglycaemia. Aims: To report the first case of genetically confirmed CHI in Singapore from a heterozygous paternally inherited ABCC8 mutation. Methods/Results: A term male infant presented with severe hyperinsulinaemic hypoglycaemia (HH) after birth and failed medical treatment with diazoxide and octreotide. Genetic testing (paternally inherited mutation in ABCC8/p.D1472N) suggested focal disease, but due to the unavailability of 18F-DOPA-PET/CT to confirm focal disease, a partial pancreatectomy was performed. Interestingly, histology of the resected pancreatic tissue showed changes typical of diffuse disease. Conclusion: Heterozygous paternally inherited ABCC8/KCNJ11 mutations can lead to diffuse or focal CHI. Learning points HH is a cause of severe hypoglycaemia in the newborn period. Paternal mutations in ABCC8/KCNJ11 can lead to diffuse or focal disease. 18F-DOPA-PET/CT scan is the current imaging of choice for localising focal lesions. Gallium-68 tetra-aza-cyclododecane-N N′N″N-‴-tetra-acetate octreotate PET scan is not a useful imaging tool for localising focal lesions. The molecular mechanism by which a heterozygous ABCC8 mutation leads to diffuse disease is currently unclear. Focal lesions are curable by lesionectomy and so genetic studies in patients with HH must be followed by imaging using 18F-DOPA-PET/CT scan.

Rationale for Total Pancreatectomy for Carcinoma of the Pancreatic Head

1966 ◽  
Vol 274 (11) ◽  
pp. 599-602 ◽  
Author(s):  
John J. Collins ◽  
John E. Craighead ◽  
John R. Brooks
Keyword(s):  
Total Pancreatectomy ◽  
Pancreatic Head
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