A Multicenter Experience with Long-Acting Somatostatin Analogues in Patients with Congenital Hyperinsulinism

Background/Aims: Congenital hyperinsulinism (CHI) is a rare disease characterized by recurrent severe hypoglycemia. In the diffuse form of CHI, pharmacotherapy is the preferred choice of treatment. Long-acting somatostatin analogues have been used in children as off-label medication. However, the efficacy, outcomes, and adverse effect profiles of long-acting somatostatin analogues have not been described in multicentered studies. The aim of this retrospective study is to summarize the experience with long-acting somatostatin analogues in a large group of children with CHI. Methods: Data were obtained retrospectively from 27 patients with CHI who received long-acting somatostatin analogues in 6 different centers in Europe. These included information on glycemic stability, auxology, and adverse effect profile in clinical follow-up assessments. Results: Blood glucose control improved in most patients (89%). No life-threatening side effects occurred. Thirteen patients (48%) experienced side effects; in 3 patients (11%), the side effects were the main reason for discontinuation of the treatment. The most frequent side effect was elevated liver enzymes (n = 10, 37%). Conclusion: Long-acting somatostatin analogues are effective in glycemic control of patients with CHI. However, in 37% of all patients increased liver enzymes were observed. It is important to monitor liver function in all patients receiving long-acting somatostatin analogue therapy. (C) 2017 S. Karger AG, Base

Families’ Experiences of Continuous Glucose Monitoring in the Management of Congenital Hyperinsulinism: A Thematic Analysis

Background and AimsIn patients with congenital hyperinsulinism (CHI), recurrent hypoglycaemia can lead to longstanding neurological impairments. At present, glycaemic monitoring is with intermittent fingerprick blood glucose testing but this lacks utility to identify patterns and misses hypoglycaemic episodes between tests. Although continuous glucose monitoring (CGM) is well established in type 1 diabetes, its use has only been described in small studies in patients with CHI. In such studies, medical perspectives have been provided without fully considering the views of families using CGM. In this qualitative study, we aimed to explore families’ experiences of using CGM in order to inform future clinical strategies for the management of CHI.MethodsTen patients with CHI in a specialist centre used CGM for twelve weeks. All were invited to participate. Semi-structured interviews were conducted with nine families in whom patient ages ranged between two and seventeen years. Transcripts of the audio-recorded interviews were analysed using an inductive thematic analysis method.ResultsAnalysis revealed five core themes: CGM’s function as an educational tool; behavioural changes; positive experiences; negative experiences; and design improvements. Close monitoring and retrospective analysis of glucose trends allowed for enhanced understanding of factors that influenced glucose levels at various times of the day. Parents noted more hypoglycaemic episodes than previously encountered through fingerprick tests; this new knowledge prompted modification of daily routines to prevent and improve the management of hypoglycaemia. CGM use was viewed favourably as offering parental reassurance, reduced fingerprick tests and predictive warnings. However, families also reported unfavourable aspects of alarms and questionable accuracy at low glucose levels. Adolescents were frustrated by the short proximity range for data transmission resulting in the need to always carry a separate receiver. Overall, families were positive about the use of CGM but expected application to be tailored to their child’s medical condition.ConclusionsPatients and families with CHI using CGM noticed trends in glucose levels which motivated behavioural changes to reduce hypoglycaemia with advantages outweighing disadvantages. They expected CHI-specific modifications to enhance utility. Future design of CGM should incorporate end users’ opinions and experiences for optimal glycaemic monitoring of CHI

Unravelling the genetic causes of mosaic islet morphology in congenital hyperinsulinism

Congenital hyperinsulinism (CHI) causes dysregulated insulin secretion which can lead to life-threatening hypoglycaemia if not effectively managed. CHI can be sub-classified into three distinct groups: diffuse, focal and mosaic pancreatic disease. Whilst the underlying causes of diffuse and focal disease have been widely characterised, the genetic basis of mosaic pancreatic disease is not known. To gain new insights into the underlying disease processes of mosaic-CHI we studied the islet tissue histopathology derived from limited surgical resection from the tail of the pancreas in a patient with CHI. The underlying genetic aetiology was investigated using a combination of high depth next-generation sequencing, microsatellite analysis and p57kip2 immunostaining. Histopathology of the pancreatic tissue confirmed the presence of a defined area associated with marked islet hypertrophy and a cytoarchitecture distinct from focal CHI but compatible with mosaic CHI localised to a discrete region within the pancreas. Analysis of DNA extracted from the lesion identified a de novo mosaic ABCC8 mutation and mosaic paternal uniparental disomy which were not present in leukocyte DNA or the surrounding unaffected pancreatic tissue. This study provides the first description of two independent disease-causing somatic genetic events occurring within the pancreas of an individual with localised mosaic CHI. Our findings increase knowledge of the genetic causes of islet disease and provide further insights into the underlying developmental changes associated with β-cell expansion in CHI

Standardised practices in the networked management of congenital hyperinsulinism: a UK national collaborative consensus

Congenital hyperinsulinism (CHI) is a condition characterised by severe and recurrent hypoglycaemia in infants and young children caused by inappropriate insulin over-secretion. CHI is of heterogeneous aetiology with a significant genetic component and is often unresponsive to standard medical therapy options. The treatment of CHI can be multifaceted and complex, requiring multidisciplinary input. It is important to manage hypoglycaemia in CHI promptly as the risk of long-term neurodisability arising from neuroglycopaenia is high. The UK CHI consensus on the practice and management of CHI was developed to optimise and harmonise clinical management of patients in centres specialising in CHI as well as in non-specialist centres engaged in collaborative, networked models of care. Using current best practice and a consensus approach, it provides guidance and practical advice in the domains of diagnosis, clinical assessment and treatment to mitigate hypoglycaemia risk and improve long term outcomes for health and well-being

HYPO-CHEAT’s aggregated weekly visualisations of risk reduce real world hypoglycaemia

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

Continuous glucose monitoring for children with hypoglycaemia:Evidence in 2023

In 2023, childhood hypoglycaemia remains a major public health problem and significant risk factor for consequent adverse neurodevelopment. Irrespective of the underlying cause, key elements of clinical management include the detection, prediction and prevention of episodes of hypoglycaemia. These tasks are increasingly served by Continuous Glucose Monitoring (CGM) devices that measure subcutaneous glucose at near-continuous frequency. While the use of CGM in type 1 diabetes is well established, the evidence for widespread use in rare hypoglycaemia disorders is less than convincing. However, in the few years since our last review there have been multiple developments and increased user feedback, requiring a review of clinical application. Despite advances in device technology, point accuracy of CGM remains low for children with non-diabetes hypoglycaemia. Simple provision of CGM devices has not replicated the efficacy seen in those with diabetes and is yet to show benefit. Machine learning techniques for hypoglycaemia prevention have so far failed to demonstrate sufficient prediction accuracy for real world use even in those with diabetes. Furthermore, access to CGM globally is restricted by costs kept high by the commercially-driven speed of technical innovation. Nonetheless, the ability of CGM to digitally phenotype disease groups has led to a better understanding of natural history of disease, facilitated diagnoses and informed changes in clinical management. Large CGM datasets have prompted re-evaluation of hypoglycaemia incidence and facilitated improved trial design. Importantly, an individualised approach and focus on the behavioural determinants of hypoglycaemia has led to real world reduction in hypoglycaemia. In this state of the art review, we critically analyse the updated evidence for use of CGM in non-diabetic childhood hypoglycaemia disorders since 2020 and provide suggestions for qualified use.</p