Familial hyperinsulinaemic hypoglycaemia with epileptic syndrome, cognitive impairment and detected mutation of the ABCC 8 (SUR1) gene: a case report

Hyperinsulinaemic hypoglycaemia (HH) occurs as a consequence of unregulated insulin secretion from pancreatic beta cells. It is the most common cause of severe and prolonged hypoglycemia in newborns. HH is a major risk factor for brain damage and subsequent neurological disability, which is why the identification, rapid diagnosis, and timely treatment of patients with HH are essential for the prevention of brain damage. The present case gives a brief description of a patient with congenital HH with an established mutation in the ABCC8 gene encoding the SUR1 subunit of the K-ATP channel. The genealogical tree, the clinical picture, the diagnostic cascade, the neurological consequences and their development in dynamics are considered, with special emphasis on the epileptic syndrome and mental status. Advances in molecular genetics, radiological imaging techniques, conservative treatment, or laparoscopic surgery may completely change the clinical approach to children with severe congenital forms of HH.

Safety and efficacy of low-dose diazoxide in small-for-gestational-age infants with hyperinsulinaemic hypoglycaemia

ObjectivesDiazoxide (DZX) is the drug of choice for treating hyperinsulinaemic hypoglycaemia (HH), and it has potentially serious adverse effects. We studied the safety and efficacy of low-dose DZX in small-for-gestational-age (SGA) infants with HH.DesignAn observational cohort study from 1 September 2014 to 31 September 2020.SettingA tertiary Women’s and Children’s Hospital in Singapore.PatientsAll SGA infants with HH.InterventionDiazoxide, at 3–5 mg/kg/day.Main outcome measuresShort-term outcomes; adverse drug events and fasting studies to determine ‘safe to go home’ and ‘resolution’ of HH.ResultsAmong 71 836 live births, 11 493 (16%) were SGA. Fifty-six (0.5%) SGA infants with HH were identified, of which 27 (47%) with a mean gestational age of 36.4±2 weeks and birth weight of 1942±356 g required DZX treatment. Diazoxide was initiated at 3 mg/kg/day at a median age of 10 days. The mean effective dose was 4.6±2.2 mg/kg/day, with 24/27 (89%) receiving 3–5 mg/kg/day. Generalised hypertrichosis occurred in 2 (7.4%) and fluid retention in 1 (3.7%) infant. A fasting study was performed before home while on DZX in 26/27 (96%) cases. Diazoxide was discontinued at a median age of 63 days (9–198 days), and resolution of HH was confirmed in 26/27 (96%) infants on passing a fasting study.ConclusionOur study demonstrates that low-dose DZX effectively treats SGA infants with HH as measured by fasting studies. Although the safety profile was excellent, minimal adverse events were still observed with DZX, even at low doses.

Glucokinase activating mutation causing hypoglycaemia diagnosed late in adult who fasts for Ramadhan

Summary Activating mutation of glucokinase gene (GCK) causes resetting of insulin inhibition at a lower glucose threshold causing hyperinsulinaemic hypoglycaemia (GCK-HH). This is the first reported case who tolerated years of regular fasting during Ramadhan, presenting only with seizure and syncope now. We describe a case with GCK gene variant p.T65I diagnosed in a 51-year-old woman with hypoglycaemia unawareness even at glucose level of 1.6 mmol/L. Insulin and C-peptide levels during hypoglycaemia were suggestive of hyperinsulinism, but at a day after intravenous glucagon, hypoglycaemia occurred with low insulin and C-peptide levels, pointing against insulinoma as the underlying aetiology. Imaging studies of the pancreas and calcium arterial stimulation venous sampling were unremarkable. A review of old medical records revealed asymptomatic hypoglycaemia years ago. Genetic testing confirmed activating mutation of GCK. Hypoglycaemia was successfully controlled with a somatostatin analogue. This case highlights the importance of consideration of genetic causes of hypoglycaemia in adulthood, especially when imaging is uninformative. Learning points Consider genetic causes of endogenous hyperinsulinism hypoglycaemia in adulthood, especially when imaging is uninformative. Late presentation of activating mutation of GCK can occur because of hypoglycaemia unawareness. Long-acting somatostatin analogue may be useful for the treatment of activating mutation of GCK causing hypoglycaemia. Depending on the glucose level when the blood was taken, and the threshold of glucose-stimulated insulin release (GSIR), the serum insulin and C-peptide levels may be raised (hyperinsulinaemic) or low (hypoinsulinaemic) in patients with activating mutation of GCK. Glucagon may be useful to hasten the process of unmasking the low insulin level during hypoglycaemia below the GSIR level of which insulin released is suppressed.

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

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

Breast cancer in multiple endocrine neoplasia type 1 (MEN1)

Summary A 38-year-old female was identified as carrying a heterozygous pathogenic MEN1 variant (c.1304delG) through predictive genetic testing, following a diagnosis of familial hyperparathyroidism. Routine screening for parathyroid and pituitary disease was negative. However, cross-sectional imaging by CT revealed a 41 mm pancreatic tail mass. Biopsy via endoscopic ultrasound confirmed the lesion to be a well-differentiated (grade 1) pancreatic neuroendocrine tumour (pNET) with MIB1<1%. Biochemically, hyperinsulinaemic hypoglycaemia was confirmed following an overnight fast, which was subsequently managed by diet alone prior to definitive surgery. Pre-operative work-up with octreotide SPECT CT demonstrated avid tracer uptake in the pancreatic lesion and, unexpectedly, a focal area of uptake in the left breast. Further investigation, and subsequent mastectomy, confirmed ductal carcinoma in situ pT2 (23 mm) grade 1, N0 (ER positive; HER2 negative). Following mastectomy, our patient underwent a successful distal pancreatectomy to resect the pNET. Loss of heterozygosity (LOH) at the MEN1 locus was found in both the breast tumour and pNET, thereby in keeping with a 'two-hit' hypothesis of oncogenesis, a suggestive but non-definitive clue for causation. To obtain further support for a causative relationship between MEN1 and breast cancer, we undertook a detailed review of the published literature which overall supports the notion that breast cancer is a MEN1-related malignancy that presents at a younger age and histologically, is typically of ductal subtype. Currently, clinical guidance regarding breast cancer surveillance in MEN1 does not exist and further research is required to establish a clinical and cost-effective surveillance strategy). Learning points We describe a case of pNET and breast cancer diagnosed at a young age of 38 years in a patient who is heterozygous for a pathogenic MEN1 variant. Loss of the wild-type allele was seen in both breast tissue and pNET specimen. Breast cancer may be an under-recognised MEN1-associated malignancy that presents at a younger age than in the general population with a relative risk of 2–3. Further research is required to determine the cost-effectiveness of breast cancer surveillance approach at a younger age in MEN1 patients relative to the general population .

Hyperinsulinaemic hypoglycaemia in non-anaesthetized Göttingen minipigs induces a counter-regulatory endocrine response and electrocardiographic changes

The potentially fatal cardiovascular effects of hypoglycaemia are not well understood and large animal models of the counter-regulatory responses and cardiovascular consequences of insulin-induced hypoglycaemia are needed to understand the mechanisms in humans. The aim of this study was to develop a human-like minipig model of hypoglycaemia including healthy and diabetic pigs to investigate endocrine, electrocardiographic and platelet effects. Hypoglycaemia was induced using a hyperinsulinaemic, hypoglycaemic clamp and an insulin bolus protocol. Plasma glucose, glucagon, C-peptide, insulin, epinephrine and platelet aggregation responses were measured before, during and after hypoglycaemia. Continuous electrocardiographic recordings were obtained. Hypoglycaemia at a plasma glucose concentration of 0.8–1.0 mM in the clamp induced 25-fold increase in epinephrine and sixfold and threefold increase in glucagon for healthy and diabetic pigs, respectively. The hypoglycaemic clamp induced QTc-interval prolongation and increase in cardiac arrhythmias. In the bolus approach, the non-diabetic group reached plasma glucose target of 1.5 mM and QTc-interval was prolonged after insulin injection, but before glucose nadir. The diabetic group did not reach hypoglycaemic target, but still demonstrated QTc-interval prolongation. These results demonstrate effects of hyperinsulinaemic hypoglycaemia closely resembling human physiology, indicating the minipig as a translational animal model of counter-regulatory endocrine and myocardial effects of hypoglycaemia.

Diazoxide-responsive hyperinsulinaemic hypoglycaemia in tyrosinaemia type 1

Summary Tyrosinaemia type 1 (TT1) is a rare inherited disorder of amino acid metabolism typically presenting with liver failure and renal tubular dysfunction. We describe three individuals with TT1 and transient hyperinsulinaemic hypoglycaemia (HH). Two siblings with TT1 and acute liver dysfunction were diagnosed with hyperinsulinaemic hypoglycaemia in the neonatal period. Both siblings were successfully treated with diazoxide/chlorthiazide and treatment was gradually weaned and stopped after 8 and 6 months of age respectively. The third patient presented with a neonatal liver failure with mild cholestasis, coagulopathy, fundus haemorrhages, vitamin A and E deficiency and hyperinsulinaemic hypoglycaemia. He maintained euglycaemia on high dose diazoxide (5–12 mg/kg/day) but developed pulmonary hypertension at 12 weeks of age. After discontinuation of diazoxide, he continued maintaining his blood glucose (BG) within the normal range. Although histological abnormalities of the pancreas including beta-cell hyperplasia are well documented, the exact mechanism of excessive insulin secretion in TT1 is not well understood. It may be related to the accumulation of toxic metabolites in the target organs including pancreas. Therefore, in patients with TT1 and persistent hypoglycaemia beyond the recovery of the acute liver failure, it is important to exclude hyperinsulinism which is usually transient and can be successfully treated with diazoxide and chlorothiazide. Further studies are required to determine which factors contribute to excessive insulin secretion in patients with TT1. Learning points Every child with TT1 should be monitored for signs and symptoms of hypoglycaemia and screened for HH at the time of real hypoglycaemia. If hypoglycaemic episodes persist even after improvement of liver function, hyperinsulinism should be suspected. Treatment with diazoxide is effective, however, children need to be monitored closely for possible side effects. The pathophysiological mechanism of hyperinsulinism in children with TT1 is not elucidated yet and further studies are required to determine which factors contribute to excessive insulin secretion in patients with TT1.

Multifocal insulinoma secondary to insulinomatosis: persistent hypoglycaemia despite total pancreatectomy

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.