The prevalence of Vitamin D deficiency is higher in adult survivors of childhood cancer.

BACKGROUND: It is unclear whether the rate of vitamin D deficiency in paediatric cancer survivors is higher than in the background population, and whether this is of pathological significance. PATIENTS AND METHODS: 25OHD was measured in a previously studied group of 208 survivors (n = 108 paediatric 5-17 years, n = 99 adults 18-39 years) and compared with paediatric (5-17 years; n = 132) and adult controls (25-35 years; n = 1393 from the AusDiab cohort) adjusted for age and gender. Relationships with treatment factors (irradiation, bone marrow transplantation and intensity of treatment) along with overweight/obesity (defined by BMI), abdominal adiposity (waist:height ratio >0·5) and hyperinsulinism or abnormal glucose tolerance (HI/aGT) were sought. RESULTS: 25OHD concentrations were similar in paediatric survivors compared with controls (64·3 ± 21·6 nmol/l vs 66·3 ± 22·8 nmol/l), with no effect of age or gender. Adjusted for gender, rates of 25OHD deficiency (<50 nmol/l) were higher in adult survivors compared with AusDiab controls (42·4% vs 20·8%; P < 0·001). Apart from time since diagnosis (P = 0·03), no relationship with treatment factors was detected. In multivariate regression analysis, abdominal adiposity (P = 0·001), but not overweight/obesity by BMI status nor HI/aGT, was associated with significantly lower 25OHD concentrations. CONCLUSIONS: Adult survivors are at increased risk of abnormalities in vitamin D compared to the background population, probably reflecting longer time since diagnosis. Like others, we have not identified any contributory treatment-related factors. Vitamin D deficiency does not appear to be associated with the development of abnormal glucose tolerance in this population.

Home blood sodium monitoring, sliding-scale fluid prescription and subcutaneous DDAVP for infantile diabetes insipidus with impaired thirst mechanism.

BACKGROUND/AIMS: Infants with diabetes insipidus (DI), especially those with impaired thirst mechanism or hypothalamic hyperphagia, are prone to severe sodium fluctuations, often requiring hospitalization. We aimed to avoid dangerous fluctuations in serum sodium and improve parental independence. METHODS: A 16-month old girl with central DI, absent thirst mechanism and hyperphagia following surgery for hypothalamic astrocytoma had erratic absorption of oral DDAVP during chemotherapy cycles. She required prolonged hospitalizations for hypernatremia and hyponatremic seizure. Intensive monitoring of fluid balance, weight and clinical assessment of hydration were not helpful in predicting serum sodium. Discharge home was deemed unsafe. Oral DDAVP was switched to subcutaneous (twice-daily injections, starting with 0.01mcg/dose, increasing to 0.024mcg/dose). The parents adjusted daily fluid allocation by sliding-scale, according to the blood sodium level (measured by handheld i-STAT analyser, Abbott). We adjusted the DDAVP dose if fluid allocation differed from maintenance requirements for 3 consecutive days. RESULTS: After 2.5 months, sodium was better controlled, with 84% of levels within reference range (135-145 mmol/L) vs. only 51% on the old regimen (p = 0.0001). The sodium ranged from 132-154 mmol/L, compared to 120-156 on the old regimen. She was discharged home. CONCLUSION: This practical regimen improved sodium control, parental independence, and allowed discharge home.

Once daily insulin detemir in cystic fibrosis with insulin deficiency.

The aim of this study was to determine if once daily insulin detemir reverses decline in weight and lung function in patients with cystic fibrosis (CF). 12 patients with early insulin deficiency and six with CF related diabetes (aged 7.2-18.1 years) were treated for a median of 0.8 years. Changes in weight and lung function following treatment were compared to pretreatment changes. Before treatment, the change in weight SD score (ΔWtSDS), percentage of predicted forced expiratory volume in 1 s (Δ%FEV(1)) and percentage of predicted forced vital capacity (Δ%FVC) declined in the whole study population (-0.45±0.38, -7.9±12.8%, -5.8±14.3%) and in the subgroup with early insulin deficiency (-0.41±0.43, -9.8±9.3%, -6.8±10.3%). Following treatment with insulin ΔWtSDS, Δ%FEV(1) and Δ%FVC significantly improved in the whole study population (+0.18±0.29 SDS, p=0.0001; +3.7±10.6%, p=0.007; +5.2±12.7%, p=0.013) and in patients with early insulin deficiency (+0.22±0.31 SDS, p=0.003; +5.3±11.5%, p=0.004; +5.8±13.4%, p=0.024). Randomised controlled trials are now needed.

Persistently autoantibody negative (PAN) type 1 diabetes mellitus in children.

BACKGROUND: Autoantibody-negative children diagnosed with type 1 diabetes might have unrecognized monogenic or type 2 diabetes. RESEARCH DESIGN AND METHODS: At diagnosis of type 1 diabetes (between ages 0.5 and 16.3 yr, n = 470), autoantibodies [glutamic acid decarboxylase (GAD), insulinoma-associated protein 2 (IA2), insulin autoantibodies (IAA), and/or islet cell antibody (ICA)] were positive (ab+) in 330 and negative in 37 (unknown in 103). Autoantibody-negative patients were retested at median diabetes duration of 3.2 yr (range 0.9-16.2) for autoantibodies (GAD, IA2, ZnT8), human leukocyte antigen (HLA) typing, non-fasting C-peptide, and sequencing of HNF4A, HNF1A, KCNJ11, and INS. RESULTS: Nineteen (5% of 367) remained persistently autoantibody negative (PAN), 17 were positive on repeat testing (PORT), and 1 refused retesting. No mutations were found in PORT. One PAN was heterozygous for P112L mutation in HNF1A and transferred from insulin to oral gliclazide. Another PAN transferred to metformin and the diagnosis was revised to type 2 diabetes. The remaining 17 PAN were indistinguishable from the ab+ group by clinical characteristics. HLA genotype was at high risk for type 1 diabetes in 82% of remaining PAN and 100% of PORT. After excluding patients with diabetes duration <1 yr, C-peptide was detectable more frequently in the remaining PAN (7/16) and PORT (6/17) than in a random selection of ab+ (3/28, p = 0.03). CONCLUSIONS: The diagnosis of type 1 diabetes should be reevaluated in PAN patients, because a subset has monogenic or type 2 diabetes. The remaining PAN have relatively preserved C-peptide compared with ab+, suggesting slower ß-cell destruction, but a very high frequency of diabetogenic HLA, implying that type 1B (idiopathic) diabetes is rare.

Prevention of hyponatremia during maintenance intravenous fluid administration: a prospective randomized study of fluid type versus fluid rate.

OBJECTIVES: To determine the importance of sodium content versus administration rate of intravenous fluids in the development of hyponatremia in postoperative children. STUDY DESIGN: In this prospective, randomized, nonblinded study, 124 children admitted for surgery received 0.9% (NS) or 0.45% (N/2) saline solution at 100% or 50% maintenance rates. Plasma electrolytes, osmolality, and ADH at induction of anesthesia were compared with values 8 hours (T(8)), and 24 hours (T(24); n = 67) after surgery. Blood glucose and ketones were measured every 4 hours. Electrolytes and osmolality were measured in urine samples. RESULTS: Plasma sodium concentrations fell in both N/2 groups at T(8) (100%: -1.5 +/- 2.3 mmol/L 50%: -1.9 +/- 2.0 mmol/L; P < .01) with hyponatremia more common than in the NS groups at T(8) (30% vs 10%; P = .02) but not T(24). Median plasma antidiuretic hormone concentrations increased 2- to 4-fold during surgery (P < or = .001) and only reattained levels at induction of anesthesia by T(24) in the N/2 100% group. On multiple linear regression analysis, fluid type, not rate determined risk of hyponatremia (P < .04). Two children on 100% developed SIADH (1NS). Fourteen (23%; 7NS) on 50% maintenance were assessed as dehydrated. Dextrose content was increased in 18 for hypoglycemia or ketosis. CONCLUSIONS: The risk of hyponatremia was decreased by isotonic saline solution but not fluid restriction.

Insulin allergy desensitization with simultaneous intravenous insulin and continuous subcutaneous insulin infusion.

Persistent 'IgE-mediated' insulin allergy (type 1 allergy) (1), unresponsive to changes in insulin type or the use of antihistamines, necessitates desensitization. A number of case reports (2-7) and recent reviews (8, 9) have demonstrated that desensitization can be achieved with continuous subcutaneous insulin infusion (CSII), but in type 1 diabetes mellitus, the need to slowly increase insulin dose from sub-therapeutic levels competes with the need for glycaemic control and suppression of ketogenesis. Tolerance to intravenous (IV) insulin despite persistent life-threatening allergic reactions to subcutaneous human insulin (bolus or CSII) has been recently described (10). We present the cases of two unrelated 9-yr-old boys with persistent generalized urticarial reactions to subcutaneous injections of all available insulin types, despite treatment with oral antihistamines. After failed rapid desensitization to insulin delivered by either subcutaneous injection or CSII, the concurrent use of IV insulin allowed desensitization to CSII over 5-6 d.

The addition of rosiglitazone to insulin in adolescents with type 1 diabetes and poor glycaemic control: a randomized-controlled trial.

OBJECTIVE: To evaluate the effect of rosiglitazone, an insulin sensitizer, on glycaemic control and insulin resistance in adolescents with type 1 diabetes mellitus (T1DM) RESEARCH DESIGN AND METHODS: Randomized, double-blind, placebo-controlled crossover trial of rosiglitazone (4 mg twice daily) vs. placebo (24 wk each, with a 4 wk washout period). Entry criteria were diabetes duration >1 yr, age 10-18 yr, puberty (>or=Tanner breast stage 2 or testicular volume >4 mL), insulin dose >or=1.1 units/kg/day, and haemoglobin A1c (HbA1c) >8%. Responses to rosiglitazone were compared with placebo using paired t-tests. RESULTS: Of 36 adolescents recruited (17 males), 28 completed the trial. At baseline, age was 13.6 +/- 1.8 yr, HbA1c 8.9 +/- 0.96%, body mass index standard deviation scores (BMI-SDS) 0.94 +/- 0.74 and insulin dose 1.5 +/- 0.3 units/kg/day. Compared with placebo, rosiglitazone resulted in decreased insulin dose (5.8% decrease vs. 9.4% increase, p = 0.02), increased serum adiponectin (84.8% increase vs. 26.0% decrease, p < 0.01), increased cholesterol (+0.5 mmol/L vs. no change, p = 0.02), but no significant change in HbA1c (-0.3 vs. -0.1, p = 0.57) or BMI-SDS (0.08 vs. 0.04, p = 0.31). Insulin sensitivity was highly variable in the seven subjects who consented to euglycaemic hyperinsulinaemic clamps. There were no major adverse effects attributable to rosiglitazone. CONCLUSION: The addition of rosiglitazone to insulin did not improve HbA1c in this group of normal weight adolescents with T1DM.

Hyperinsulinemia, impaired glucose tolerance, and diabetes mellitus in survivors of childhood cancer: prevalence and risk factors.

CONTEXT: Hyperinsulinism and its associated metabolic abnormalities, including diabetes mellitus (DM), have been reported in long-term survivors of childhood cancer, mainly after bone marrow transplant (BMT); however, the predisposing factors are unclear, and early markers have not been identified. METHODS: The prevalence of overweight/obesity, abdominal adiposity and hyperinsulinemia (HI), impaired glucose tolerance (IGT), or DM was examined prospectively in 248 survivors of childhood cancer (36 prepubertal, 88 pubertal, and 124 adult subjects; 67 BMT) at a median of 12.9 yr (2.3-33.6) after diagnosis and compared with healthy controls. Potential risk factors for the development of HI, IGT, or DM were sought. RESULTS: Overweight/obesity was not increased when comparing subjects with controls; however, the prevalence of abdominal adiposity in prepubertal and pubertal subjects was roughly doubled (P < or = 0.04). Fasting insulin concentrations were higher in prepubertal and pubertal subjects compared with their controls (P < 0.001) and were similar in adult and pubertal subjects. HI, IGT, or DM was detected in 39 of 212 (18%) pubertal or adult subjects (23 BMT). Ten of 88 (11%) pubertal and 14 of 124 (11%) adult subjects had IGT/DM (vs. 0 and 4.9% controls, respectively; P < 0.001). Total body irradiation, untreated hypogonadism, and abdominal adiposity emerged as independent risk factors for the development of HI, IGT, or DM in multivariate regression analysis. CONCLUSIONS: The risk factors identified suggest the need for reconsideration of BMT protocols and regular screening of survivors. The increased prevalence of abdominal adiposity among prepubertal subjects, none of whom had developed HI/IGT/DM, suggests that a waist to height ratio greater than 0.5 has potential as a clinical screening tool.

High antidiuretic hormone levels and hyponatremia in children with gastroenteritis.

OBJECTIVES: Nonosmotic antidiuretic hormone (ADH) activity can cause severe hyponatremia during involuntary fluid administration. We looked for evidence of this before and during intravenous (IV) fluid administration in children treated for gastroenteritis. METHODOLOGY: In this prospective observational study, plasma ADH, electrolytes, osmolality, and glucose were measured in 52 subjects before (T0) and 4 hours after (T4) starting 0.45% saline + 2.5% dextrose and subsequently when indicated. Hormonal markers of stress were measured at T0. Urine samples were collected to measure electrolytes and osmolality. RESULTS: The nonosmotic stimuli of ADH secretion that we identified were vomiting (50 of 52), dehydration (median: 5%; range: 3-8%), hypoglycemia (2 of 52), and raised hormonal markers of stress (mean +/- SD: cortisol, 1094 +/- 589 nmol/L; reverse triiodothyronine, 792 +/- 293 pmol/L). At T0, half the children were hyponatremic (plasma sodium concentration of < 135 mmol/L; n = 27). The median plasma ADH concentration at T0 was significantly elevated (median: 7.4 pg/mL; range: < 1.9-85.6 pg/mL). ADH was high in both hyponatremic and normonatremic children and remained high at T4 in 33 of the 52 children, 22 of whom were concurrently hyponatremic. At T4, mean plasma sodium concentration was unchanged in the hyponatremic children but was 2.6 mmol/L (+/-2.0) lower in those who were initially normonatremic. Urine tonicity was high compared with 0.45% saline in 16 of 19 children at baseline and in 20 of 37 children after 3 to 12 hours of IV fluids. CONCLUSIONS: Nonosmotic stimuli of ADH secretion are frequent in children with gastroenteritis. Their persistence during IV-fluid administration predisposes to dilutional hyponatremia. The use of hypotonic saline for deficit replacement needs to be reassessed.

Transient reduction in the posterior pituitary bright signal preceding water intoxication in a malnourished child.

We describe a 4 year-old boy with hypothalamic dysfunction and weight loss, attributed to psychosocial deprivation. Reduced intensity of the posterior pituitary bright signal (PPBS) on MRI, associated with a normal urinary concentrating ability, was documented in the 24 hours prior to the development of the syndrome of inappropriate secretion of antidiuretic hormone (ADH) and severe hyponatraemia. The PPBS was normal on MRI 2 months later, following weight gain and resolution of the other hypothalamic abnormalities. This report shows that the abnormalities of ADH associated with decreased intensity of the PPBS include increased secretion and abnormal regulation as well as ADH deficiency. The association of osmotically unregulated ADH secretion with undernutrition and stress suggests that particuar caution should be used when fluid intake in such children is not driven by thirst.