Henrik Thybo Christesen

Vitamin D and diabetes: its importance for beta cell and immune function.

Experimental evidence indicates that vitamin D may play a role in the defense against type 1 diabetes (T1D) as well as type 2 diabetes (T2D). Epidemiological data have established a link between vitamin D deficiency and an increased incidence of both T1D and T2D, whereas early and long-term vitamin D supplementation may decrease the risk of these disorders. The protective effects of vitamin D are mediated through the regulation of several components such as the immune system and calcium homeostasis. However, an increasing amount of evidence suggests that vitamin D also affects beta cells directly thereby rendering them more resistant to the types of cellular stress encountered during T1D and T2D. This review evaluates the role of vitamin D signaling in the pathogenesis of T1D and T2D with a special emphasis on the direct effects of vitamin D on pancreatic beta cells.

Expanding the Spectrum of Mutations in GH1 and GHRHR: Genetic Screening in a Large Cohort of Patients with Congenital Isolated Growth Hormone Deficiency

CONTEXT It is estimated that 3-30% of cases with isolated GH deficiency (IGHD) have a genetic etiology, with a number of mutations being reported in GH1 and GHRHR. The aim of our study was to genetically characterize a cohort of patients with congenital IGHD and analyze their characteristics. PATIENTS AND METHODS A total of 224 patients (190 pedigrees) with IGHD and a eutopic posterior pituitary were screened for mutations in GH1 and GHRHR. To explore the possibility of an association of GH1 abnormalities with multiple pituitary hormone deficiencies, we have screened 62 patients with either multiple pituitary hormone deficiencies (42 pedigrees), or IGHD with an ectopic posterior pituitary (21 pedigrees). RESULTS Mutations in GH1 and GHRHR were identified in 41 patients from 21 pedigrees (11.1%), with a higher prevalence in familial cases (38.6%). These included previously described and novel mutations in GH1 (C182X, G120V, R178H, IVS3+4nt, a>t) and GHRHR (W273S, R94L, R162W). Autosomal dominant, type II IGHD was the commonest form (52.4%), followed by type IB (42.8%) and type IA (4.8%). Patients with type II IGHD had highly variable phenotypes. There was no difference in the endocrinology or magnetic resonance imaging appearance between patients with and without mutations, although those with mutations presented with more significant growth failure (height, -4.7 +/- 1.6 SDS vs. -3.4 +/- 1.7 SDS) (P = 0.001). There was no apparent difference between patients with mutations in GH1 and GHRHR. CONCLUSIONS IGHD patients with severe growth failure and a positive family history should be screened for genetic mutations; the evolving endocrinopathy observed in some of these patients suggests the need for long-term follow-up.

The impact of vitamin D on pregnancy: a systematic review

Hypovitaminosis D is common in pregnancy. To systematically review the evidence on vitamin D‐dependent pregnancy outcomes, PubMed and Embase were searched for randomized control trials, cohort and case–control studies. In randomized control trials (n = 7), larger doses of vitamin D resulted in higher 25‐hydroxylated vitamin D (25OHD) levels (n = 6), increased maternal weight gain (n = 1), and fewer classical vitamin D deficiency symptoms (n = 1). In observational studies (n = 32), lower vitamin D intake, or low 25OHD‐levels, were associated with adverse fertility parameters (n = 2), preeclampsia (n = 5), gestational diabetes or higher blood glucose (n = 6), bacterial vaginosis (n = 4), primary cesarean section (n = 1), none (n = 3) or a few days’ (n = 2) shorter gestation, and postpartum depression (n = 1). Studies with few participants having low 25OHD did not identify an association to preeclampsia (n = 5) or gestational diabetes (n = 2). Increased odds of pregnancy‐associated breast cancer with 25OHD >25.8 nmol/L were observed (n = 1). In conclusion, an effect of vitamin D on several pregnancy outcomes is suggested.

Activating glucokinase (GCK) Mutations as a cause of medically responsive congenital hyperinsulinism: prevalence in children and characterisation of a novel GCK mutation

OBJECTIVE Activating glucokinase (GCK) mutations are a rarely reported cause of congenital hyperinsulinism (CHI), but the prevalence of GCK mutations is not known. METHODS From a pooled cohort of 201 non-syndromic children with CHI from three European referral centres (Denmark, n=141; Norway, n=26; UK, n=34), 108 children had no K(ATP)-channel (ABCC8/KCNJ11) gene abnormalities and were screened for GCK mutations. Novel GCK mutations were kinetically characterised. RESULTS In five patients, four heterozygous GCK mutations (S64Y, T65I, W99R and A456V) were identified, out of which S64Y was novel. Two of the mutations arose de novo, three were dominantly inherited. All the five patients were medically responsive. In the combined Danish and Norwegian cohort, the prevalence of GCK-CHI was estimated to be 1.2% (2/167, 95% confidence interval (CI) 0-2.8%) of all the CHI patients. In the three centre combined cohort of 72 medically responsive children without K(ATP)-channel mutations, the prevalence estimate was 6.9% (5/72, 95% CI 1.1-12.8%). All activating GCK mutations mapped to the allosteric activator site. The novel S64Y mutation resulted in an increased affinity for the substrate glucose (S(0.5) 1.49+/-0.08 and 7.39+/-0.05 mmol/l in mutant and wild-type proteins respectively), extrapolating to a relative activity index of approximately 22 compared with the wild type. CONCLUSION In the largest study performed to date on GCK in children with CHI, GCK mutations were found only in medically responsive children who were negative for ABCC8 and KCNJ11 mutations. The estimated prevalence (approximately 7%) suggests that screening for activating GCK mutations is warranted in those patients.

Proposal for a standardized protocol for 18F-DOPA-PET (PET/CT) in congenital hyperinsulinism

a Department of Pediatrics and Neonatology, Otto von Guericke University Magdeburg, Magdeburg , and b Department of Pediatric Endocrinology, Charité University of Medicine Berlin, Berlin , Germany; c Department of Pediatrics, Odense University Hospital, Odense , Denmark; d Department of Pediatrics, Hôpital Necker Enfants Malades, Paris , France; e London Centre for Paediatric Endocrinology and Metabolism, Great Ormond Street Hospital for Children, London , UK; f Department of Nuclear Medicine/PET Centre, University Medical Centre Groningen, Groningen , The Netherlands; g Department of Oncology and Radiotherapy, Turku University Central Hospital, Turku , Finland; h PET Centre Berlin, Berlin , Germany; i Department of Pediatrics, King Abdilaziz Medical City, Riyadh , Saudi Arabia; j University Children’s Hospital for Pediatric Endocrinology and Diabetology, Helsinki , Finland; k Department of Pathology, Cliniques Universitaires St Luc, UCL, Brussels , Belgium; l CEA Service Hospitalier Frédéric Joliot, Orsay , France; m Department of Pediatrics, University of Zurich, Zurich , Switzerland, and n Department of Pediatric Surgery, Hôpital Necker Enfants Malades, Paris , France

Epidemiology and prevention of caustic ingestion in children

A total of 102 children less than 16 years of age admitted for caustic ingestion in the period 1976–1991 were registrated. The annual incidence rate of hospitalizatiotl was 10.8:100000 for the city of Aarhus, Denmark. Esophageal burns occurred with a frequency of 5.0:100000 per year. Ninety‐four percent of the children were less than 5 years old. For this age group, the incidence rates of admission and esophageal burns were 34.6:100 000 and 15.8:100 000, respectively. All ingestions were accidental. The incidence rates of esophageal burns in children 0–4 years old (p= 0.019) decreased significantly during the period studied. The cause of this decrease is not clear, but a change in the spectrum of household products and the gradual introduction of child‐proof caps are possible explanations. To minimize the frequency of accidents, an information campaign directed specifically at parents of toddlers is recommended. Information material should stress that caustics should always be inaccessible to children and stored separately, and should never be decanted.

The impact of vitamin D in pregnancy on extraskeletal health in children: a systematic review

The impact of maternal vitamin D status in pregnancy on the extraskeletal health of the offspring has become a “hot topic” with a potential for cost‐beneficial prevention. The objective of this study was to systematically review the level I and II evidence. PubMed, Embase and Cochrane databases were searched using the MeSH terms “vitamin D” AND “pregnancy” until 1 January 2012. The search was limited to randomized controlled trials (evidence level I) and observational studies (evidence level II) in humans and in the English language. Papers reporting on vitamin D supplementation in combination with other supplements, or not reporting on 25OHD or outcomes of the offspring were excluded. Six randomized controlled trials and 24 observational studies were finally included. In randomized controlled studies, vitamin D supplementation resulted in increased birthweight in one study, but showed no effect in five other studies. In cohort and case–control studies, higher vitamin D intake, or higher 25OHD, was associated with increased birthweight in large studies only, and modified by vitamin D receptor polymorphisms and by race (U‐shaped in Caucasians in one unconfirmed study). The risks of HIV mother‐to‐child transmission, rhinitis symptoms and eczema were lower. Data were conflicting on the effect on respiratory infections and wheezing, whereas U‐shaped associations to inhalant allergen‐specific IgE at five years and to schizophrenia were reported in unconfirmed studies. The risk of type 1 diabetes at 15 years was lower or unchanged. It is concluded that observational studies suggest an effect of vitamin D on several outcomes. U‐Shaped associations warrant caution.

Prediction of complications following unintentional caustic ingestion in children. Is endoscopy always necessary

The records of 115 children hospitalized following caustic ingestion over an 18.5‐year period from 1976 to 1994 were reviewed. The relationship between types of product ingested, signs and symptoms, degree of esophageal injury and complications was analyzed. All complications were the result of strong alkali ingestion (sensitivity = 1.0). Among the 102 incident patients, 36.8% of lye ingestions resulted in complications, whereas only 2.7% (one) of automatic dishwasher detergent (ADD) ingestions caused any complications (p < 0.01). Endoscopy 6h to 4 days after injury was accurate in predicting or identifying complications in all types of strong alkali ingestions. In lye ingestions, endoscopy was not superior to the test, “one or more signs or symptoms” in predicting complications (predictivity = 1.0). Endoscopy is recommended to establish or confirm a prognosis, or to identify acute respiratory complications, in symptomatic ingestions of lye or ammonia water, in children with respiratory symptoms, and in rare cases of severe symptoms following ADD or strong acid ingestion. It is suggested that children who are non‐symptomatic following unintentional ingestions are not at risk of complications and do not need endoscopic examination. Causlic ingestion, children, complication, diagnostic test, endoscopy, esophagus, unintentional

Hyperinsulinaemic hypoglycaemia: biochemical basis and the importance of maintaining normoglycaemia during management

In patients with suspected hyperinsulinaemic hypoglycaemia, blood glucose concentrations should be maintained within the normal range during routine management Hyperinsulinaemic hypoglycaemia (HH) is a major cause of recurrent and persistent hypoglycaemia in infancy and childhood.1 Rapid diagnosis, avoidance of recurrent and repeated episodes of hypoglycaemia and prompt management of the hypoglycaemia are vital in preventing brain damage and mental retardation.2 Unfortunately, a large proportion of children with HH still develop brain damage as a consequence of delayed diagnosis and subsequent management. HH can be either congenital or secondary to certain risk factors (such as intrauterine growth retardation). Congenital hyperinsulinism involves either defects in the genes ABCC8 and KCNJ11 (encoding for the two proteins SUR1 and KIR6.2 of the pancreatic β cell KATP channel, respectively) or abnormalities in the enzymes glucokinase, glutamate dehydrogenase and short chain acyl-CoA dehydrogenase ( SCHAD ). Loss of function mutations in the genes ABCC8 and KCNJ11 cause the most severe forms of HH which are usually medically unresponsive. HH is also observed in newborns with intrauterine growth retardation, in infants with perinatal asphyxia, in infants of diabetic (gestational and insulin dependent) mothers, in some infants with Beckwith-Weidemann syndrome and, more recently, in infants with no predisposing factors.3–6 In most of these conditions, the HH is a transient phenomenon and resolves spontaneously. However, some small for gestational age and appropriate for gestational age infants can have prolonged hyperinsulinaemic hypoglycaemia which requires treatment with diazoxide, persists for several months and then resolves spontaneously.7,8 Recognition of this group of patients is important as they are fully responsive to treatment with oral diazoxide. The underlying mechanisms of the HH in these patient groups are unclear at present. The biochemical basis of HH (congenital and secondary) involves dysregulated insulin secretion with …

Parity and tanned white skin as novel predictors of vitamin D status in early pregnancy: a population-based cohort study.

In pregnancy, vitamin D insufficiency and deficiency, defined as serum 25‐hydroxyvitamin D (25(OH)D) <50 nM, and <25 nM, respectively, may have adverse effects for both mother and child. Prevalence estimates, and identification of subgroups at special risk, may be useful for the planning of preventive strategies.