Somatostatin receptors in congenital hyperinsulinism:Biology to bedside

Congenital hyperinsulinism (CHI), although a rare disease, is an important cause of severe hypoglycemia in early infancy and childhood, causing preventable morbidity and mortality. Prompt diagnosis and appropriate treatment is necessary to prevent hypoglycaemia mediated brain damage. At present, the medical treatment of CHI is limited to diazoxide as first line and synthetic somatostatin receptor ligands (SRLs) as second line options; therefore understanding somatostatin biology and treatment perspectives is important. Under healthy conditions, somatostatin secreted from pancreatic islet δ-cells reduces insulin release through somatostatin receptor induced cAMP-mediated downregulation and paracrine inhibition of β- cells. Several SRLs with extended duration of action are now commercially available and are being used off-label in CHI patients. Efficacy remains variable with the present generation of SRLs, with treatment effect often being compromised by loss of initial response and adverse effects such as bowel ischaemia and hepatobiliary dysfunction. In this review we have addressed the biology of the somatostatin system contexualised to CHI. We have discussed the clinical use, limitations, and complications of somatostatin agonists and new and emerging therapies for CHI

Pasireotide treatment for severe congenital hyper-insulinism due to a homozygous ABCC8 mutation

ABCC8 and KCJN11 mutations cause the most severe diazoxide-resistant forms of congenital hyperinsulinism (CHI). Somatostatin analogues are considered as secondline treatment in diazoxide-unresponsive cases. Current treatment protocols include the first-generation somatostatin analogue octreotide, although pasireotide, a second-generation somatostatin analogue, might be more effective in reducing insulin secretion. Herein we report the first off-label use of pasireotide in a boy with a severe therapy-resistant form of CHI due to a homozygous ABCC8 mutation. After partial pancreatectomy, hyperinsulinism persisted; in an attempt to prevent further surgery, off-label treatment with pasireotide was initiated. Short-acting pasireotide treatment caused high blood glucose level shortly after injection. Long-acting pasireotide treatment resulted in more stable glycemic control. No side effects (e.g., central adrenal insufficiency) were noticed during a 2-month treatment period. Because of recurrent hypoglycemia despite a rather high carbohydrate intake, the boy underwent near-total pancreatectomy at the age of 11 months. In conclusion, pasireotide treatment slightly improved glycemic control without side effects in a boy with severe CHI. However, the effect of pasireotide was not sufficient to prevent near-total pancreatectomy in this case of severe CHI

Abnormal glucose homeostasis and fasting intolerance in patients with congenital porto-systemic shunts

In physiological glucose homeostasis, the liver plays a crucial role in the extraction of glucose from the portal circulation and storage as glycogen to enable release through glycogenolysis upon fasting. In addition, insulin secreted by the pancreas is partly eliminated from the systemic circulation by hepatic first-pass. Therefore, patients with a congenital porto-systemic shunt present a unique combination of (a) postabsorptive hyperinsulinemic hypoglycaemia (HH) because of decreased insulin elimination and (b) fasting (ketotic) hypoglycaemia because of decreased glycogenolysis. Patients with porto-systemic shunts therefore provide important insight into the role of the portal circulation and hepatic function in different phases of glucose homeostasis

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

Abnormal glucose homeostasis and fasting intolerance in patients with congenital porto-systemic shunts

In physiological glucose homeostasis, the liver plays a crucial role in the extraction of glucose from the portal circulation and storage as glycogen to enable release through glycogenolysis upon fasting. In addition, insulin secreted by the pancreas is partly eliminated from the systemic circulation by hepatic first-pass. Therefore, patients with a congenital porto-systemic shunt present a unique combination of (a) postabsorptive hyperinsulinemic hypoglycaemia (HH) because of decreased insulin elimination and (b) fasting (ketotic) hypoglycaemia because of decreased glycogenolysis. Patients with porto-systemic shunts therefore provide important insight into the role of the portal circulation and hepatic function in different phases of glucose homeostasis

Clinical presentation and long-term follow-up of dopamine beta hydroxylase deficiency

Dopamine beta hydroxylase (DBH) deficiency is an extremely rare autosomal recessive disorder with severe orthostatic hypotension, that can be treated with L-threo-3,4-dihydroxyphenylserine (L-DOPS). We aimed to summarize clinical, biochemical, and genetic data of all world-wide reported patients with DBH-deficiency, and to present detailed new data on long-term follow-up of a relatively large Dutch cohort. We retrospectively describe 10 patients from a Dutch cohort and 15 additional patients from the literature. We identified 25 patients (15 females) from 20 families. Ten patients were diagnosed in the Netherlands. Duration of follow-up of Dutch patients ranged from 1 to 21 years (median 13 years). All patients had severe orthostatic hypotension. Severely decreased or absent (nor)epinephrine, and increased dopamine plasma concentrations were found in 24/25 patients. Impaired kidney function and anemia were present in all Dutch patients, hypomagnesaemia in 5 out of 10. Clinically, all patients responded very well to L-DOPS, with marked reduction of orthostatic complaints. However, orthostatic hypotension remained present, and kidney function, anemia, and hypomagnesaemia only partially improved. Plasma norepinephrine increased and became detectable, while epinephrine remained undetectable in most patients. We confirm the core clinical characteristics of DBH-deficiency and the pathognomonic profile of catecholamines in body fluids. Impaired renal function, anemia, and hypomagnesaemia can be part of the clinical presentation. The subjective response to L-DOPS treatment is excellent and sustained, although the neurotransmitter profile in plasma does not normalize completely. Furthermore, orthostatic hypotension as well as renal function, anemia, and hypomagnesaemia improve only partially

Pulmonary arterial hypertension in congenital cardiac disease - the need for refinement of the Evian-Venice classification

Pulmonary hypertension associated with congenital systemic-to-pulmonary shunts has been classified, in the Evian-Venice classification, as Pulmonary Arterial Hypertension, which includes a heterogeneous group of conditions. Emerging options for treatment of patients with pulmonary arterial hypertension are related to those with the idiopathic form of the disease, but may also improve quality of life and survival in patients with pulmonary arterial hypertension associated with congenital cardiac disease. Despite the evident similarities in pulmonary vascular disease, it is important also to recognise the differences between patients in whom pulmonary arterial hypertension is the consequence of systemic-to-pulmonary shunts as opposed to those with other conditions. Patients with pulmonary hypertension associated with congenital cardiac disease themselves constitute a heterogeneous population, in which generallsation may be hazardous. Specific considerations need to be given to the type of cardiac diagnosis, the prognosis and evolution of pulmonary vascular disease, and the circulatory physiology before embarking on new strategies for medical treatment in the individual patient. In this review, we highlight the features that require specific attention in these patients. In addition, we discuss briefly the data currently available on the effectiveness of the new anti-proliferative drugs in patients with the Eisenmenger syndrome

Treprostinil in advanced experimental pulmonary hypertension:Beneficial outcome without reversed pulmonary vascular remodeling

Introduction: Beneficial effects of treprostmil, a stable prostacyclin analogue, were demonstrated in patients with pulmonary arterial hypertension (PAH). Although regression of pulmonary vascular remodeling has been suggested as therapeutic mechanism, its mode of action remains unknown. Methods: Flow-associated PAH was created in rats by injection of monocrotaline (60 mg/kg) combined with an abdominal aortocaval shunt. Subsequently, rats were treated with subcutaneous treprostinil (50 ng/kg/min, treated; n = 8) or saline (untreated; n = 9). A control group underwent sham-surgery (n = 8). Animals were sacrificed at symptoms of cardiac failure, together with their matched controls. Results: Dyspnea and weight loss determined the moment of sacrifice in 8/9 untreated animals (89%) versus in one of eight treated animals (13%; log-rank test survival curves; P = 0.02). Mean pulmonary arterial pressure increased in the model (42 +/- 2 mm Hg in untreated vs. 18 +/- 1 in controls; P <0.0 1) and decreased by 8 mm Hg after therapy (34 +/- 3 mm Hg, P = 0.04 vs. untreated). No effects of treatment on right ventricular hypertrophy could be demonstrated. Quantitative morphometry of pre- and intra-acinar pulmonary arteries revealed no effects of treatment on vessel histopathology. Conclusions: Treprostinil treatment improved clinical course and ameliorated symptoms of heart failure in a model of advanced PAR However, beneficial effects were not associated with reversed structural remodelling of the pulmonary vasculature

Prostacyclin therapy increases right ventricular capillarisation in a model for flow-associated pulmonary hypertension

Pulmonary hypertension, and consequently right ventricular failure, complicates several congenital heart defects. Although intervention in the prostacyclin-thromboxane ratio is known to improve outcome, the underlying mechanism is not clear. Therefore, effects of acetyl salicylic acid and iloprost are studied in an animal model for flow-associated pulmonary hypertension. Male Wistar rats with flow-associated pulmonary hypertension, an aortocaval shunt in addition to monocrotaline induced pulmonary hypertension, were treated with low-dose aspirin (25 mg/kg/day) or iloprost (72 microg/kg/day). Effects on pulmonary hemodynamics and pulmonary vascular remodeling as well as right ventricular hemodynamics and remodeling were evaluated. Ninety percent (n=7/8) of the untreated pulmonary hypertensive rats developed dyspnea and pleural fluid, whereas this was seen in 50% (n=4/8, ns) and 10% (n=1/8, P<0.05 vs. untreated animals) of the aspirin and iloprost-treated rats, respectively. This could not be attributed to changes in pulmonary artery pressure, wall-lumen ratio of the pulmonary vasculature or right ventricular hypertrophy. However, both therapies restored reduced right ventricular capillary to myocyte ratio in pulmonary hypertensive rats (0.95+/-0.10 in untreated rats vs. 1.38+/-0.18 in control animals; P<0.05, and 1.32+/-0.11 in aspirin-treated and 1.29+/-0.9 in iloprost-treated rats; both P<0.05 vs. non-treated animals), which was associated with improved right ventricular contractility (iloprost). Thus, interventions in the prostacyclin-thromboxane metabolism improve outcome in rats with flow-associated pulmonary hypertension. However, these effects may be attributed to effects on cardiac rather than on pulmonary vascular remodeling