Introduction: Diazoxide is the first line and only Federal Drug Agency approved pharmacological agent for the treatment of hyperinsulinism. Its use has increased over the years to include patients with various genetic forms of hyperinsulinism, perinatal stress hyperinsulinism and infants of diabetic mothers with more babies than ever being exposed to this therapy. Methods: We performed a retrospective analysis of 194 patients with hyperinsulinism in our clinic and looked for those who had experienced serious adverse events (SAE) including pulmonary hypertension and neutropenia. We compared the rates of SAE in the different types of hyperinsulinism. Results: Out of 194 patients with hyperinsulinism, 165 (85.1%) were treated with diazoxide. There were 17 SAEs in 16 patients including 8 cases of pulmonary hypertension and 8 of neutropenia. These data show that overall the frequency of SAE associated with diazoxide use is 9.7%, but that those with perinatal stress hyperinsulinism have a much higher rate than those with genetic forms of hyperinsulinism (16.7 vs. 3.6%; p = 0.01). We also found diazoxide is associated with pulmonary hypertension (4.8% of patients treated). Although more patients with perinatal stress hyperinsulinism (7.6%) were affected than genetic hyperinsulinism (1.2%), the difference was not significant (p = 0.088). Conclusion: The rate of SAEs associated with (not necessarily caused by) diazoxide has been demonstrated. The rate of SAE in newborns with perinatal stress hyperinsulinism is significantly higher than that of otherwise healthy babies with genetic forms of hyperinsulinism, suggesting that caution should be used when prescribing diazoxide to this population. This information should help balance the risk benefit of treatment and provide guidance on screening for these complications in the population of treated patients.
The aim of this study is to assess the radiation absorbed dose of 18F-Fluoro-L-DOPA derived from the Positron Emission Tomography (PET) images of infants age ranging from 2 weeks– 32 weeks and a median age of 4.84 weeks (Mean 10.0 ± 10.3 weeks) with congenital hyperinsulinism.MethodsAfter injecting 25.6 ± 8.8 MBq (0.7 ± 0.2 mCi) of 18F-Fluoro-L-DOPA intravenously, three static PET scans were acquired at 20, 30, and 40 min post injection in 3-D mode on 10 patients (6 male, 4 female) with congenital hyperinsulinism. Regions of interest (ROIs) were drawn over several organs visible in the reconstructed PET/CT images and time activity curves (TACs) were generated. Residence times were calculated using the TAC data. The radiation absorbed dose for the whole body was calculated by entering the residence times in the OLINDA/EXM 1.0 software.ResultsThe mean residence times for the 18F-Fluoro-L-DOPA in the liver, lungs, kidneys, muscles, and pancreas were 11.54 ± 2.84, 1.25 ± 0.38, 4.65 ± 0.97, 17.13 ± 2.62, and 0.89 ± 0.34 min, respectively. The mean effective dose equivalent for 18F-Fluoro-L-DOPA was 0.40 ± 0.04 mSv/MBq. The CT scan used for attenuation correction delivered an additional radiation dose of 5.7 mSv. The organs receiving the highest radiation absorbed dose from 18F-Fluoro-L-DOPA were the urinary bladder wall (2.76 ± 0.95 mGy/MBq), pancreas (0.87 ± 0.30 mGy/MBq), liver (0.34 ± 0.07 mGy/MBq), and kidneys (0.61 ± 0.11 mGy/MBq). The renal system was the primary route for the radioactivity clearance and excretion.ConclusionsThe estimated radiation dose burden from 18F-Fluoro-L-DOPA is relatively modest to newborns.
Introduction Congenital hyperinsulinism is characterized by abnormal regulation of insulin secretion from the pancreas causing profound hypoketotic hypoglycemia and is the leading cause of persistent hypoglycemia in infants and children. The main objective of this study is to highlight the different mechanisms to interpret the 18 F-DOPA PET scans and how this can influence outcomes. Materials and methods After 18 F-Fluoro-L-DOPA was injected intravenously into 50 subjects’ arm at a dose of 2.96–5.92 MBq/kg, three to four single-bed position PET scans were acquired at 20, 30, 40 and 50-minute post injection. The radiologist interpreted the scans for focal and diffuse hyperinsulinism using a visual interpretation method, as well as determining the Standard Uptake Value ratios with varying cut-offs. Results Visual interpretation had the combination of the best sensitivity and positive prediction values. Conclusions In patients with focal disease, SUV ratios are not as accurate in identifying the focal lesion as visual inspection, and cases of focal disease may be missed by those relying on SUV ratios, thereby denying the patients a chance of cure. We recommend treating patients with diazoxide-resistant hyperinsulinism in centers with dedicated multidisciplinary team comprising of at least a pediatric endocrinologist with a special interest in hyperinsulinism, a radiologist experienced in interpretation of 18 F-Fluoro-L-DOPA PET/CT scans, a histopathologist with experience in frozen section analysis of the pancreas and a pancreatic surgeon experienced in partial pancreatectomies in patients with hyperinsulinism.
Leucine‐rich repeat containing 10 (LRRC10) is a cardiac‐specific protein expressed in embryonic and adult hearts and plays critical roles in cardiac development and function. Recently we have demonstrated that the Lrrc10‐null (Lrrc10‐/‐) mice develop dilated cardiomyopathy and ventricular myocytes from Lrrc10‐/‐ mice exhibit reduced L‐type Ca2+ channel (LTCC) current (ICa,L) density. However, the precise role of LRRC10 protein in the regulation of LTCC function in the cardiomyocytes is unknown. To investigate the regulatory role of LRRC10 on Cav1.2 channel function, we co‐expressed the Myc tagged LRRC10 (LRRC10‐Myc), heamagglutinin tagged Cav1.2 (Cav1.2‐HA) and auxiliary Cavβ2CN4 subunit in HEK293 cells and performed co‐immunoprecipitation (co‐IP) on lysates using either anti‐HA, anti‐Myc antibody or control IgG. Western blot analysis demonstrated that Cav1.2 and LRRC10 associated with one another. Also, the auxiliary Cavβ2C subunit and LRRC10 did not co‐IP with one another suggesting that the LRRC10 may directly interact with the Cav1.2 subunit. A single point mutation H150A or triple point mutations Y104A, W127A and H150A mutation in LRRC10 disrupted the LRRC10 protein association with Cav1.2. Co‐IP analysis using mouse ventricular homogenates demonstrated that LRRC10 and Cav1.2 subunit are associated with one another. Additionally, double immunogold labeling and electron microscopy analysis revealed that LRRC10 and Cav1.2 proteins are co‐localized at T‐tubules in the ventricular myocytes. Finally, whole‐cell patch clamp experiments performed in ventricular myocytes from Lrrc10‐/‐ mice demonstrated a significant reduction in the ICa,L density (‐2.5 0.2 pA/pF) and compared to WT myocytes (‐6 0.6 pA/pF). Furthermore, the inactivation of the ICa,L in Lrrc10‐/‐ myocytes was significantly delayed. We conclude that LRRC10 protein is a novel and essential regulator of the LTCC function in ventricular myocytes. Grant Funding Source: R01HL105713
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