Background
Hyperinsulinism (HI) due to excess and dysregulated insulin secretion is the most common cause of severe and recurrent hypoglycemia in childhood. High cerebral glucose use in the early ...hours results in a high risk of hypoglycemia in people with diabetes and carries a significant risk of brain injury. Prevention of hypoglycemia is the cornerstone of the management of HI, but the risk of hypoglycemia at night or the timing of hypoglycemia in children with HI has not been studied; thus, the digital phenotype remains incomplete and management suboptimal.
Objective
This study aims to quantify the timing of hypoglycemia in patients with HI to describe glycemic variability and to extend the digital phenotype. This will facilitate future work using computational modeling to enable behavior change and reduce exposure of patients with HI to injurious hypoglycemic events.
Methods
Patients underwent continuous glucose monitoring (CGM) with a Dexcom G4 or G6 CGM device as part of their clinical assessment for either HI (N=23) or idiopathic ketotic hypoglycemia (IKH; N=24). The CGM data were analyzed for temporal trends. Hypoglycemia was defined as glucose levels <3.5 mmol/L.
Results
A total of 449 hypoglycemic events totaling 15,610 minutes were captured over 237 days from 47 patients (29 males; mean age 70 months, SD 53). The mean length of hypoglycemic events was 35 minutes. There was a clear tendency for hypoglycemia in the early hours (3-7 AM), particularly for patients with HI older than 10 months who experienced hypoglycemia 7.6% (1480/19,370 minutes) of time in this period compared with 2.6% (2405/92,840 minutes) of time outside this period (P<.001). This tendency was less pronounced in patients with HI who were younger than 10 months, patients with a negative genetic test result, and patients with IKH. Despite real-time CGM, there were 42 hypoglycemic events from 13 separate patients with HI lasting >30 minutes.
Conclusions
This is the first study to have taken the first step in extending the digital phenotype of HI by describing the glycemic trends and identifying the timing of hypoglycemia measured by CGM. We have identified the early hours as a time of high hypoglycemia risk for patients with HI and demonstrated that simple provision of CGM data to patients is not sufficient to eliminate hypoglycemia. Future work in HI should concentrate on the early hours as a period of high risk for hypoglycemia and must target personalized hypoglycemia predictions. Focus must move to the human-computer interaction as an aspect of the digital phenotype that is susceptible to change rather than simple mathematical modeling to produce small improvements in hypoglycemia prediction accuracy.
Growth hormone (GH), insulin-like growth factor (IGF)-I and insulin have potent growth-promoting and anabolic actions. Their potential involvement in tumor promotion and progression has been of ...concern for several decades. The evidence that GH, IGF-I and insulin can promote and contribute to cancer progression comes from various sources, including transgenic and knockout mouse models and animal and human cell lines derived from cancers. Assessments of the GH-IGF axis in healthy individuals followed up to assess cancer incidence provide direct evidence of this risk; raised IGF-I levels in blood are associated with a slightly increased risk of some cancers. Studies of human diseases characterized by excess growth factor secretion or treated with growth factors have produced reassuring data, with no notable increases in de novo cancers in children treated with GH. Although follow-up for the vast majority of these children does not yet extend beyond young adulthood, a slight increase in cancers in those with long-standing excess GH secretion (as seen in patients with acromegaly) and no overall increase in cancer with insulin treatment, have been observed. Nevertheless, long-term surveillance for cancer incidence in all populations exposed to increased levels of GH is vitally important.
We have recently published on the limited effectiveness of sirolimus as a treatment option for hypoglycaemia as a consequence of hyperinsulinism. Our data oppose the view that mTOR inhibitors provide ...new opportunities for the treatment of patients with hyperinsulinism. We are not convinced by the argument that any benefit for some patients outweighs the potential and later long-term problems that accompany mTOR inhibition in the neonate. We also express the opinion that caution must be taken when repurposing/repositioning therapies in the field of rare disease.
Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycemia in infants and children, and carries a considerable risk of neurological damage and developmental delays if ...diagnosis and treatment are delayed. Despite rapid advances in diagnosis and management, long-term developmental outcomes have not significantly improved in the past years. CHI remains a disease that is associated with significant morbidity, and psychosocial and financial burden for affected families, especially concerning the need for constant blood glucose monitoring throughout patients' lives.
In this review, we discuss the key clinical challenges and unmet needs, and present insights on patients' and families' perspective on their daily life with CHI. Prevention of neurocognitive impairment and successful management of patients with CHI largely depend on early diagnosis and effective treatment by a multidisciplinary team of specialists with experience in the disease.
To ensure the best outcomes for patients and their families, improvements in effective screening and treatment, and accelerated referral to specialized centers need to be implemented. There is a need to develop a wider range of centers of excellence and networks of specialized care to optimize the best outcomes both for patients and for clinicians. Awareness of the presentation and the risks of CHI has to be raised across all professions involved in the care of newborns and infants. For many patients, the limited treatment options currently available are insufficient to manage the disease effectively, and they are associated with a range of adverse events. New therapies would benefit all patients, even those that are relatively stable on current treatments, by reducing the need for constant blood glucose monitoring and facilitating a personalized approach to treatment.
Easypod-connect™ for childhood growth disorders is a unique connected system that enables transmission of injection adherence information for recombinant human growth hormone (r-hGH). Although this ...system has the potential to facilitate greater adherence, observational studies have shown declining adherence over prolonged periods when used without additional support. Supplemental nurse practitioner support has been envisaged but not investigated; in this study, we have undertaken feasibility analysis of nurse-led virtual reviews (NVR) in combination with easypod-connect™ in a single centre using quantitative and qualitative analyses.
We aimed to test feasibility by assessing compliance with NVR, height standard deviation score (SDS) gain, adherence improvement and patient opinions.
Patients using easypod™ r-hGH were recruited prospectively to a 12-month study with two telephone NVR appointments in addition to standard of care in-person hospital outpatient visits. A subset was recruited for a semi-structured interview for qualitative thematic analysis.
Forty-three patients of median (range) age 10.7 (6.7, 15.2) were recruited for a period of 1.1 (0.7, 1.8) years. Thirty-three (76.7%) patients were fully compliant with NVR integration with easypod-connect™, establishing feasibility. Median (inter-quartile range, IQR) height SDS improved from -1.85 (-2.44, -1.37) to -1.48 (-2.14, -1.07) (p<0.001) while adherence remained similar in the majority from study start 96.5 (88.8, 100.0) to end 99.0 (94.0, 100.0). Qualitative analysis identified themes supporting patient benefit: practicalities of appointments, perceived purpose and significance of virtual reviews, and the importance of optimising growth. Four patients complained of injection pain, of whom two switched to an alternative r-hGH device.
Our study has demonstrated the feasibility of nurse-led virtual review integration with easypod-connect™ in a mixed methods study, laying the foundation for research in larger groups over longer periods. Nurse practitioner supported application of easypod-connect™ offers the potential for improved growth outcomes in all r-hGH devices providing adherence information.
Congenital hyperinsulinism (CHI) is a significant cause of hypoglycaemia in neonates and infants with the potential for permanent neurologic injury. Accurate calculations of the incidence of rare ...diseases such as CHI are important as they inform health care planning and can aid interpretation of genetic testing results when assessing the frequency of variants in large-scale, unselected sequencing databases. Whilst minimal incidence rates have been calculated for four European countries, the incidence of CHI in the UK is not known. In this study we have used referral rates to a central laboratory for genetic testing and annual birth rates from census data to calculate the minimal incidence of CHI within the UK from 2007 to 2016. CHI was diagnosed in 278 individuals based on inappropriately detectable insulin and/or C-peptide measurements at the time of hypoglycaemia which persisted beyond 6 months of age. From these data, we have calculated a minimum incidence of 1 in 28,389 live births for CHI in the UK. This is comparable to estimates from other outbred populations and provides an accurate estimate that will aid both health care provision and interpretation of genetic results, which will help advance our understanding of CHI.
Congenital hyperinsulinism (CHI) is a rare, genetic disease which causes persistent hypoglycaemia, typically in new-borns. Patients with the diffuse disease variant often require near-total surgical ...removal of the pancreas, causing insulin-dependent diabetes mellitus (IDDM). The CHI economic burden is currently unknown. This study aimed to estimate the annual cost of illness (COI) of CHI patients in the UK from a service provider perspective (National Health Service, NHS and Personal Social Services), and to explore cost distribution within the patient population.
The model was based on standard practice of two CHI centres of excellence. Model inputs were informed by a pragmatic literature review, NHS Reference Costs (2015-2016) and the British National Formulary (2017). Only direct costs to the NHS and Personal Social Services were considered. A prevalence-based approach was used and annual costs incurred at all ages were calculated. A deterministic sensitivity analysis (DSA; run at 10%) identified major cost drivers.
The COI of CHI patients to the NHS was £3,408,398.59 annually and average cost per patient was £2124.95. Cost distribution was skewed among CHI patients, with 5.9% of patients (95 patients in their first year of life) contributing to 61.8% (£2,105,491.07) of total costs. DSA results identified lack of response to first-line therapy and IDDM development post surgery (and associated healthcare costs) as major cost drivers.
Despite its rare disease status, estimated annual costs of CHI to the NHS were substantial. Development and management of post-surgical IDDM as a major cost driver highlights the need for effective treatments to mitigate such consequences and costs.
Background
Children with congenital hyperinsulinism (CHI) are at constant risk of hypoglycaemia with the attendant risk of brain injury. Current hypoglycaemia prevention methods centre on the ...prediction of a continuous glucose variable using machine learning (ML) processing of continuous glucose monitoring (CGM). This approach ignores repetitive and predictable behavioural factors and is dependent upon ongoing CGM. Thus, there has been very limited success in reducing real-world hypoglycaemia with a ML approach in any condition.
Objectives
We describe the development of HYPO-CHEAT (HYpoglycaemia-Prevention-thrOugh-CGM-HEatmap-Technology), which is designed to overcome these limitations by describing weekly hypoglycaemia risk. We tested HYPO-CHEAT in a real-world setting to evaluate change in hypoglycaemia.
Methods
HYPO-CHEAT aggregates individual CGM data to identify weekly hypoglycaemia patterns. These are visualised via a hypoglycaemia heatmap along with actionable interpretations and targets. The algorithm is iterative and reacts to anticipated changing patterns of hypoglycaemia. HYPO-CHEAT was compared with Dexcom Clarity's pattern identification and Facebook Prophet's forecasting algorithm using data from 10 children with CHI using CGM for 12 weeks. HYPO-CHEAT's efficacy was assessed via change in time below range (TBR).
Results
HYPO-CHEAT identified hypoglycaemia patterns in all patients. Dexcom Clarity identified no patterns. Predictions from Facebook Prophet were inconsistent and difficult to interpret. Importantly, the patterns identified by HYPO-CHEAT matched the lived experience of all patients, generating new and actionable understanding of the cause of hypos. This facilitated patients to significantly reduce their time in hypoglycaemia from 7.1% to 5.4% even when real-time CGM data was removed.
Conclusions
HYPO-CHEAT's personalised hypoglycaemia heatmaps reduced total and targeted TBR even when CGM was reblinded. HYPO-CHEAT offers a highly effective and immediately available personalised approach to prevent hypoglycaemia and empower patients to self-care.
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