Neonatal hyperinsulinism in transient and classical forms of tyrosinemia.
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ABSTRACT: Background
The spectrum of disorders associated with hyperinsulinemic hypoglycemia (HHI) has vastly increased over the past 20 years with identification of molecular, metabolic and cellular pathways involved in the regulation of insulin secretion and its actions. Hereditary tyrosinemia (HT1) is a rare metabolic disorder associated with accumulation of toxic metabolites of the tyrosine pathway due to a genetically mediated enzyme defect of fumarylacetoacetate hydrolase. Transient tyrosinemia of the newborn (TTN) is a benign condition with a maturational defect of the enzymes associated with tyrosine metabolism without any genetic abnormalities.Results
We describe two rare cases of HHI, one in a patient with HT1 and for the first time, in a patient with TTN. Each of our patients presented in the neonatal period with persistent hypoglycemia that on biochemical evaluation was consistent with HHI. Each patient received diazoxide therapy for 3.5 months and 17 months of life, respectively and HHI resolved thereafter.Conclusion
Despite the fact that HHI has been described in HT1 for several decades, no specific mechanism has been delineated. Although we considered the common embryonal origin of the liver and pancreas with the hepatotoxic effect in HT1 also impacting the latter, this was not a possible explanation for TTN. The commonality between our two patients is the accumulation of certain amino acids which are known to be insulinotropic. We therefore hypothesize that the excess of amino acids such as leucine, lysine, valine and isoleucine in our patients resulted in HHI, which was transient. Both patients responded to diazoxide. This novel presentation in TTN and the reassuring response in both HT1 and TTN to diazoxide will be useful to inform physicians about managing HHI in these patients. Further studies are required to delineate the mechanism of HHI in these infants.
SUBMITTER: Sethuram S
PROVIDER: S-EPMC8082838 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectiveThe objective was to determine whether maternal nutritional factors are associated with transient neonatal hyperinsulinism (HI).Design and settingCase control study in 4 French tertiary Obstetrics and Neonatology Departments between 2008 and 2015.MethodsSixty-seven mothers of neonates diagnosed with transient hyperinsulinism and 113 mothers of controls were included. The screening for hyperinsulinemic hypoglycemia in neonates was performed because of clinical symptoms suggestive of hypoglycemia or in the presence of conventional risk factors (small-for-gestational-age, prematurity, anoxo-ischemia, hypothermia, macrosomia, gestational diabetes). Hyperinsulinemic hypoglycemia was confirmed in the HI neonates and ruled out in the controls. This allowed for comparing maternal nutrition in cases and controls in a context of similar risk factors. One to 2 mothers of control neonates were included per case, and a food frequency questionnaire was addressed to the mothers between day 5 and day 10 after the birth of their newborn.ResultsCrude odds ratio showed that maternal weight gain, abnormal fetal rate, C-section, gender, consumption of fresh cooked vegetables, fresh fruits and fruit juices, low fat diary products, light fat products, and daily bread were significantly associated with hyperinsulinism. Maternal body mass index, hypertension, gestational diabetes, birth weight percentile, gestational age and 5-minute Apgar score were not related to HI. In a multiple backward logistic regression model, consumption of fresh cooked vegetable ≥1/day (OR = 0.33 [0.14-0.77]) and light-fat products ≥1/week (OR = 0.24 [0.08-0.71]) was protective against hyperinsulinism, whereas gestational weight gain >20 kg (OR = 9.5 [2.0-45.5]) and between 15-20 kg (OR = 4.0 [1.2-14.0]), abnormal fetal heart rate (OR = 4.4 [1.6-12.0]), and C-section (OR = 3.4 [1.3-8.9]) were risk factors.ConclusionsA diet rich in fresh cooked vegetable and reduced in fat, together with the avoidance of a high gestational weight gain may be protective against transient neonatal hyperinsulinism.
| S-EPMC5933751 | biostudies-literature
Project description:Congenital hyperinsulinism (CHI), also called hyperinsulinemic hypoglycemia (HH), is a very heterogeneous condition and represents the most common cause of severe and persistent hypoglycemia in infancy and childhood. The majority of cases in which a genetic cause can be identified have monogenic defects affecting pancreatic β-cells and their glucose-sensing system that regulates insulin secretion. However, CHI/HH has also been observed in a variety of syndromic disorders. The major categories of syndromes that have been found to be associated with CHI include overgrowth syndromes (e.g. Beckwith-Wiedemann and Sotos syndromes), chromosomal and monogenic developmental syndromes with postnatal growth failure (e.g. Turner, Kabuki, and Costello syndromes), congenital disorders of glycosylation, and syndromic channelopathies (e.g. Timothy syndrome). This article reviews syndromic conditions that have been asserted by the literature to be associated with CHI. We assess the evidence of the association, as well as the prevalence of CHI, its possible pathophysiology and its natural course in the respective conditions. In many of the CHI-associated syndromic conditions, the mechanism of dysregulation of glucose-sensing and insulin secretion is not completely understood and not directly related to known CHI genes. Moreover, in most of those syndromes the association seems to be inconsistent and the metabolic disturbance is transient. However, since neonatal hypoglycemia is an early sign of possible compromise in the newborn, which requires immediate diagnostic efforts and intervention, this symptom may be the first to bring a patient to medical attention. As a consequence, HH in a newborn or infant with associated congenital anomalies or additional medical issues remains a differential diagnostic challenge and may require a broad genetic workup.
| S-EPMC10098214 | biostudies-literature
Project description:BackgroundCongenital hyperinsulinism (CHI) is a cause of persistent hypoglycemia due to unregulated insulin secretion from pancreatic β-cells. Histologically, there are two major subgroups, focal and diffuse. Focal CHI is typically unresponsive to diazoxide and can be cured with surgical removal of the focal lesion.AimsWe report on three patients with focal CHI to illustrate the marked clinical, genetic, radiological, and histological heterogeneity.Methods and resultsThe first two patients had focal CHI due to a paternal (c.3992-9G→A) ABCC8 mutation. One of these patients was fully responsive to a small dose (5 mg/kg · d) of diazoxide, whereas the other patient was medically unresponsive. In both patients, the focal lesions were accurately localized preoperatively by [(18)F]dihydroxyphenylalanine (DOPA) positron emission tomography (PET) and surgically resected. The third patient had a paternally inherited ABCC8 (A1493T) mutation, and the initial [(18)F]DOPA PET scan indicated extensive uptake of DOPA in the body and tail of the pancreas. However, despite surgical resection of the body and tail, this patient continued to have severe CHI. A subsequent [(18)F]DOPA PET scan now showed markedly increased DOPA uptake in the remaining body and head of the pancreas. This focal lesion occupied virtually the whole of the pancreas. conclusions: These three cases illustrate that focal lesions even with the same genotype (c.3992-9G→A) may have a different clinical presentation and that [(18)F]DOPA PET scans in very large focal lesions may be difficult to interpret.
| S-EPMC7611920 | biostudies-literature
Project description:Tyrosinemia type 1 (TT1) is an inborn error of tyrosine metabolism with features including liver dysfunction, cirrhosis, and hepatocellular carcinoma; renal dysfunction that may lead to failure to thrive and bone disease; and porphyric crises. Once fatal in most infantile-onset cases, pre-symptomatic diagnosis through newborn screening (NBS) protocols, dietary management, and pharmacotherapy with nitisinone have improved outcomes. Succinylacetone provides a sensitive and specific marker for the detection of TT1 but is not universally utilized in screening protocols for the disease. Here, we report an infant transferred to our facility for evaluation and management of hyperinsulinism who subsequently developed acute-onset liver, respiratory, and renal failure around one month of life. She was found to have TT1 caused by novel pathogenic variant in fumarylacetoacetate hydrolase (c.1014 delC, p.Cys 338 Ter). Her NBS, which utilized tyrosine as a primary marker, had been reported as normal, with a tyrosine level of 151 μmol/L (reference: < 280 μmol/L). Retrospective analysis of dried blood spot samples via tandem mass spectrometry showed detectable succinylacetone ranging 4.65-10.34 μmol/L. To our knowledge, this is the first patient with TT1 whose initial presenting symptom was hyperinsulinemic hypoglycemia. The case highlights the importance of maintaining a high suspicion for metabolic disease in critically ill children, despite normal NBS. We also use the case to advocate for NBS for TT1 using succinylacetone quantitation.
| S-EPMC7422996 | biostudies-literature
Project description:IntroductionCongenital hyperinsulinism (CHI) has diffuse (CHI-D), focal (CHI-F) and atypical (CHI-A) forms. Surgical management depends on preoperative [18F]-DOPA PET/CT and intraoperative morphological differential diagnosis of CHI forms. Objective: to improve differential diagnosis of CHI forms by comparative analysis [18F]-DOPA PET/CT data, as well as cytological, histological and immunohistochemical analysis (CHIA).Materials and methodsThe study included 35 CHI patients aged 3.2 ± 2.0 months; 10 patients who died from congenital heart disease at the age of 3.2 ± 2.9 months (control group). We used PET/CT, CHIA of pancreas with antibodies to ChrA, insulin, Isl1, Nkx2.2, SST, NeuroD1, SSTR2, SSTR5, DR1, DR2, DR5; fluorescence microscopy with NeuroD1/ChrA, Isl1/insulin, insulin/SSTR2, DR2/NeuroD1 cocktails.ResultsIntraoperative examination of pancreatic smears showed the presence of large nuclei, on average, in: 14.5 ± 3.5 cells of CHI-F; 8.4 ± 1.1 of CHI-D; and 4.5 ± 0.7 of control group (from 10 fields of view, x400). The percentage of Isl1+ and NeuroD1+endocrinocytes significantly differed from that in the control for all forms of CHI. The percentage of NeuroD1+exocrinocytes was also significantly higher than in the control. The proportion of ChrA+ and DR2+endocrinocytes was higher in CHI-D than in CHI-F, while the proportion of insulin+cells was higher in CHI-A. The number of SST+cells was significantly higher in CHI-D and CHI-F than in CHI-A.ConclusionFor intraoperative differential diagnosis of CHI forms, in addition to frozen sections, quantitative cytological analysis can be used. In quantitative immunohistochemistry, CHI forms differ in the expression of ChrA, insulin, SST and DR2. The development of a NeuroD1 inhibitor would be advisable for targeted therapy of CHI.
| S-EPMC8419459 | biostudies-literature
Project description:ObjectiveAim was to identify hypotheses why adverse neurodevelopment still occurs in children with transient or persistent hyperinsulinism despite improvements in long-term treatment options during the last decades.Material and methodsA retrospective review of 87 children with transient (n=37) or persistent congenital hyperinsulinism (CHI) (n=50) was conducted at the University Children's Hospital Duesseldorf, Germany. Possible risk factors for neurodevelopmental sequelae due to hypoglycemia were analyzed with a focus on the first days after onset of disease.ResultsMedian age at follow-up was 7 years (IQR 8). Adverse neurodevelopmental outcome was seen in 34.5% (n=30) of all CHI patients. Fifteen had mildly abnormal neurodevelopment and 15 had a severe hypoglycemic brain injury. In univariate analysis, mildly abnormal neurodevelopment was associated with the diagnosis of persistent CHI (odds ratio (OR) 8.3; p=0.004) and higher birth weight (mean difference 1049 g; p<0.001). Severe hypoglycemic brain injury was associated with the diagnosis of persistent CHI (OR 5.1; p=0.013), being born abroad (OR 18.3; p<0.001) or in a lower-level maternity hospital (OR 4.8; p=0.039), and of note history of hypoglycemic seizures (OR 13.0; p=<0.001), and a delay between first symptoms of hypoglycemia and first blood glucose measurement/initiation of treatment (OR 10.7; p<0.001). Children with severe hypoglycemic brain injury had lower recorded blood glucose (mean difference -8.34 mg/dl; p=0.022) and higher birth weight than children with normal development (mean difference 829 g; p=0.012). In multivariate binary logistic regression models, lowest blood glucose <20 mg/dl (OR 134.3; p=0.004), a delay between initial symptoms and first blood glucose measurement/initiation of treatment (OR 71.7; p=0.017) and hypoglycemic seizures (OR 12.9; p=0.008) were positively correlated with severe brain injury. Analysis showed that the odds for brain injury decreased by 15% (OR 0.85; p=0.035) if the blood glucose increased by one unit.ConclusionWhile some risk factors for adverse outcome in CHI are not influenceable, others like lowest recorded blood glucose values <20 mg/dl, hypoglycemic seizures, and insufficiently-or even untreated hypoglycemia can be avoided. Future guidelines for management of neonatal hypoglycemia should address this by ensuring early identification and immediate treatment with appropriate escalation steps.
| S-EPMC7793856 | biostudies-literature
Project description:BackgroundUse of real-time continuous glucose monitoring (rtCGM) systems has been shown to be a low-pain, safe, and effective method of preventing hypoglycemia and hyperglycemia in people with diabetes of various age groups. Evidence on rtCGM use in infants and in patients with conditions other than diabetes remains limited.ObjectiveThis case study describes the off-label use of rtCGM and the use of an open-source app for glucose monitoring in a newborn with prolonged hypoglycemia secondary to transient congenital hyperinsulinism during the perinatal period.MethodsThe Dexcom G6 rtCGM system (Dexcom, Inc) was introduced at 39 hours of age. Capillary blood glucose checks were performed regularly. In order to benefit from customizable alert settings and detect hypoglycemic episodes, the open-source rtCGM app xDrip+ was introduced at 9 days of age.ResultsTime in range (45-180 mg/dL) for interstitial glucose remained consistently above 90%, whereas time in hypoglycemia (<45 mg/dL) decreased. Mean glucose was maintained above 70 mg/dL at 72 hours of life and thereafter. Daily sensor glucose profiles showed cyclic fluctuations that were less pronounced over time.ConclusionsWhile off-label use of medication is both common practice and a necessity in newborn infants, there are few examples of off-label uses of medical devices, rtCGM being a notable exception. Real-time information allowed us to better understand glycemic patterns and to improve the quality of glycemic control accordingly. Severe hypoglycemia was prevented, and measurement of serum levels of insulin and further lab diagnostics were performed much faster, while the patient's individual burden caused by invasive procedures was reduced. Greater customizability of threshold and alert settings would be beneficial for user groups with glycemic instability other than people with diabetes, and for hospitalized newborn infants in particular. Further research in the field of personal and off-label rtCGM use, efficacy studies evaluating the accuracy of low glucose readings, and studies on the differences between algorithms in translating raw sensor data, as well as customization of commercially available rtCGM systems, is needed.
| S-EPMC7748959 | biostudies-literature
Project description:Hypertrophic cardiomyopathy (HCM) in neonates is a rare and heterogeneous disorder which is characterized by hypertrophy of heart with histological and functional disruption of the myocardial structure/composition. The prognosis of HCM depends on the underlying diagnosis. In this review, we emphasize the importance to consider hyperinsulinism in the differential diagnosis of HCM, as hyperinsulinism is widely associated with cardiac hypertrophy (CH) which cannot be distinguished from HCM on echocardiographic examination. We supply an overview of the incidence and treatment strategies of neonatal CH in a broad spectrum of hyperinsulinemic diseases. Reviewing the literature, we found that CH is reported in 13 to 44% of infants of diabetic mothers, in approximately 40% of infants with congenital hyperinsulinism, in 61% of infants with leprechaunism and in 48 to 61% of the patients with congenital generalized lipodystrophy. The correct diagnosis is of importance since there is a large variation in prognoses and there are various strategies to treat CH in hyperinsulinemic diseases.Conclusion: The relationship between CH and hyperinsulism has implications for clinical practice as it might help to establish the correct diagnosis in neonates with cardiac hypertrophy which has both prognostic and therapeutic consequences. In addition, CH should be recognized as a potential comorbidity which might necessitate treatment in all neonates with known hyperinsulinism.What is Known:• Hyperinsulinism is currently not acknowledged as a cause of hypertrophic cardiomyopathy (HCM) in textbooks and recent Pediatric Cardiomyopathy Registry publications.What is New:• This article presents an overview of the literature of hyperinsulinism in neonates and infants showing that hyperinsulinism is associated with cardiac hypertrophy (CH) in a broad range of hyperinsulinemic diseases.• As CH cannot be distinguished from HCM on echocardiographic examination, we emphasize the importance to consider hyperinsulinism in the differential diagnosis of HCM/CH as establishing the correct diagnosis has both prognostic and therapeutic consequences.
| S-EPMC6942572 | biostudies-literature
Project description:K(ATP) channels regulate insulin secretion from pancreatic beta-cells. Loss- and gain-of-function mutations in the genes encoding the Kir6.2 and SUR1 subunits of this channel cause hyperinsulinism of infancy and neonatal diabetes, respectively. We report two novel mutations in the gating loop of Kir6.2 which cause neonatal diabetes with developmental delay (T293N) and hyperinsulinism (T294M). These mutations increase (T293N) or decrease (T294M) whole-cell K(ATP) currents, accounting for the different clinical phenotypes. The T293N mutation increases the intrinsic channel open probability (Po((0))), thereby indirectly decreasing channel inhibition by ATP and increasing whole-cell currents. T294M channels exhibit a dramatically reduced Po((0)) in the homozygous but not in the pseudo-heterozygous state. Unlike wild-type channels, hetT294M channels were activated by MgADP in the absence but not in the presence of MgATP; however, they are activated by MgGDP in both the absence and presence of MgGTP. These mutations demonstrate the importance of the gating loop of Kir channels in regulating Po((0)) and further suggest that Mg-nucleotide interaction with SUR1 may reduce ATP inhibition at Kir6.2.
| S-EPMC3378123 | biostudies-literature
Project description:In 1957 Sakai and Kitagawa in Japan reported the clinical and biochemical findings in a patient with tyrosinemia, tyrosyluria, liver cirrhosis, and renal rickets. Subsequently, reports were published from various countries of other patients with hepatorenal tyrosinemia (HRT). 4-Hydroxyphenylpyruvate dioxygenase deficiency was originally proposed as the cause of HRT. However, in 1977 Lindblad et al. found that succinylacetone, which accumulates in the serum and urine from patients with HRT, inhibits delta-aminolevulinic acid (ALA) dehydratase in vitro. They suggested that the primary enzyme deficiency in patients with HRT was fumarylacetoacetate hydrolase, and this was soon confirmed. Thus, the elucidation of the pathogenesis of this disease has led to the possibility that, if a reliable newborn screening method could be developed, the prognosis of these patients would be improved. Early treatment would require a diet low in phenylalanine and tyrosine, administration of 2-(2-nitoro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), and liver transplantation.
| S-EPMC3410490 | biostudies-literature