Adverse events associated with pediatric complementary and alternative medicine in the Netherlands: a national surveillance study.

Pediatric use of complementary and alternative medicine (CAM) in the Netherlands is highly prevalent. The risks of pediatric CAM use are, however, largely unknown. Therefore, a 3-year survey was carried out at the Dutch Pediatric Surveillance Unit. Pediatricians were asked to register cases of adverse events associated with pediatric CAM usage. In 3 years, 32 unique adverse events were registered. Twenty-two of these adverse events were indirect and not related to the specific CAM therapy but due to delaying, changing, or stopping of regular treatment, a deficient or very restrictive diet or an incorrect diagnosis by a CAM therapist. These events were associated with many different CAM therapies. Nine events were deemed direct adverse events like bodily harm or toxicity and one-third of them occurred in infants. Only supplements, manual therapies, and (Chinese) herbs were involved in these nine events. In one case, there was a risk of a serious adverse event but harm had not yet occurred.Conclusion: Relatively few cases of adverse events associated with pediatric CAM usage were found, mostly due to delaying or stopping conventional treatment. Nevertheless, parents, pediatricians and CAM providers should be vigilant for both direct and indirect adverse events in children using CAM, especially in infants. What's Known: • The use of complementary and alternative medicine (CAM) in children is common. • Previous surveillance studies in other countries showed severe adverse events may occur after pediatric CAM usage. What is New: • In the Netherlands CAM-related adverse events are rare but can occur, with variable etiology and severity (from mild to potentially life-threatening) • Most CAM-related adverse events are not directly the result of CAM toxicities but rather are associated with withdrawal from appropriate therapies or with providers unable to recognize health-relevant states and delaying important diagnoses.

[No harm, no foul? Adverse events in pediatric complementary and alternative medicine use]. / Baat het niet, het kan wel schaden.

In the Netherlands, children are frequently using complementary and alternative medicine (CAM), but data on adverse events are scarce. A three-year registration amongst Dutch pediatricians found 32 cases of adverse events associated with pediatric CAM use. Twenty-two children experienced adverse events that were indirectly related to the CAM treatment, such as delaying or stopping a regular treatment or diagnosis or using an unnecessary (deficient) diet. These indirect effects involved many different therapies. Nine children experienced direct adverse events such as toxicity of an ingested substance or harm due to body manipulation. Direct effects occurred after using herbal medicine, high dose vitamins or supplements, and manual-based manipulation. The authors advise physicians to be aware of potential side-effects of CAM treatment in children and inform parents regarding its use. A list of ten recommendations for parents considering the use of CAM for their children is presented.

Inhibition of mitochondrial fatty acid oxidation in vivo only slightly suppresses gluconeogenesis but enhances clearance of glucose in mice.

UNLABELLED: Mitochondrial fatty acid oxidation (mFAO) is considered to be essential for driving gluconeogenesis (GNG) during fasting. However, quantitative in vivo data on de novo synthesis of glucose-6-phosphate upon acute inhibition of mFAO are lacking. We assessed hepatic glucose metabolism in vivo after acute inhibition of mFAO by 30 mg kg(-1) 2-tetradecylglycidic acid (TDGA) in hypoketotic hypoglycemic male C57BL/6J mice by the infusion of [U-(13)C]glucose, [2-(13)C]glycerol, [1-(2)H]galactose, and paracetamol for 6 hours, which was followed by mass isotopomer distribution analysis in blood glucose and urinary paracetamol-glucuronide. During TDGA treatment, endogenous glucose production was unaffected (127 +/- 10 versus 118 +/- 7 micromol kg(-1) minute(-1), control versus TDGA, not significant), but the metabolic clearance rate of glucose was significantly enhanced (15.9 +/- 0.9 versus 26.3 +/- 1.1 mL kg(-1) minute(-1), control versus TDGA,P < 0.05). In comparison with control mice, de novo synthesis of glucose-6-phosphate (G6P) was slightly decreased in TDGA-treated mice (108 +/- 19 versus 85 +/- 6 micromol kg(-1) minute(-1), control versus TDGA, P < 0.05). Recycling of glucose was decreased upon TDGA treatment (26 +/- 14 versus 12 +/- 4 micromol kg(-1) minute(-1), control versus TDGA, P < 0.05). Hepatic messenger RNA (mRNA) levels of genes encoding enzymes involved in de novo G6P synthesis were unaltered, whereas glucose-6-phosphate hydrolase mRNA expressions were increased in TDGA-treated mice. Glucokinase and pyruvate kinase mRNA levels were significantly decreased, whereas pyruvate dehydrogenase kinase isozyme 4 expression was increased 30-fold; this suggested decreased glycolytic activity. CONCLUSION: Acute pharmacological inhibition of mFAO using TDGA had no effect on endogenous glucose production and only a marginal effect on de novo G6P synthesis. Hence, fully active mFAO is not essential for maintenance of hepatic GNG in vivo in fasted mice.

Pregnancies in glycogen storage disease type Ia.

OBJECTIVE: Reports on pregnancies in women with glycogen storage disease type Ia (GSD-Ia) are scarce. Because of improved life expectancy, pregnancy is becoming an important issue. We describe 15 pregnancies by focusing on dietary treatment, biochemical parameters, and GSD-Ia complications. STUDY DESIGN: Carbohydrate requirements (milligrams per kilogram per minute), triglyceride and uric acid levels, liver ultrasonography, and creatinine clearance were investigated before, during, and after pregnancy. Data from the newborn infants were obtained from the records. RESULTS: In the first trimester, a significant increase in carbohydrate requirements was observed (P = .007). Most patients had acceptable triglyceride and uric acid levels during pregnancy. No increase in size or number of adenomas was seen. In 3 of 4 patients, a decrease in glomerular filtration rate was observed after pregnancy. In 3 pregnancies, lactic acidosis developed during delivery with severe multiorgan failure in 1. All but 1 of the children are healthy and show good psychomotor development. CONCLUSION: Successful pregnancies are possible in patients with GSD-Ia, although specific GSD-Ia-related risks are present.

[A neonate with acute swelling of hands and feet]. / Een zuigeling met acute zwelling van handen en voeten.

A 4-week-old girl presented with acute swelling of hands and feet preceded by a red facial rash. In the days before formula feeding was gradually introduced. This proved to be a rare but severe generalized allergic reaction to cow milk.

Renal function in glycogen storage disease type I, natural course, and renopreservative effects of ACE inhibition.

BACKGROUND AND OBJECTIVES: Renal failure is a major complication in glycogen storage disease type I (GSD I). We studied the natural course of renal function in GSD I patients. We studied differences between patients in optimal and nonoptimal metabolic control and possible renoprotective effects of angiotensin converting enzyme inhibition. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Thirty-nine GSD I patients that visited our clinic were studied. GFR and effective renal plasma flow (ERPF) were measured by means of I(125) iothalamate and I(131) hippuran clearance and corrected for body surface area. Microalbuminuria was defined as >2.5 mg albumin/mmol creatinine and proteinuria as >0.2 g protein per liter. Optimal metabolic control was present when blood glucoses were >3.5 mmol/L, urine lactate/creatinine ratios <0.06 mmol/mmol, triglycerides <6.0 mmol/L, and uric acid concentrations <450 micromol/L. RESULTS: Quadratic regression analysis showed a biphasic pattern in the course of GFR and ERPF related to age. Microalbuminuria was observed significantly less frequently in the patients with optimal metabolic control compared with the patients with nonoptimal metabolic control. A significant decrease in GFR was observed after starting ACE inhibition. CONCLUSIONS: This study describes a biphasic pattern of the natural course of GFR and ERPF in GSD I patients, followed by the development of microalbuminuria and proteinuria. Optimal metabolic control has a renoprotective effect on the development of microalbuminuria and proteinuria in GSD I patients. Treatment with ACE inhibitors significantly decreases the GFR, especially in GSD I patients with glomerular hyperfiltration.

Increased de novo lipogenesis and delayed conversion of large VLDL into intermediate density lipoprotein particles contribute to hyperlipidemia in glycogen storage disease type 1a.

Glycogen storage disease type 1a (GSD-1a) is a metabolic disorder characterized by fasting-induced hypoglycemia, hepatic steatosis, and hyperlipidemia. The mechanisms underlying the lipid abnormalities are largely unknown. To investigate these mechanisms seven GSD-1a patients and four healthy control subjects received an infusion of [1-(13)C]acetate to quantify cholesterogenesis and lipogenesis. In a subset of patients, [1-(13)C]valine was given to assess lipoprotein metabolism and [2-(13)C]glycerol to determine whole body lipolysis. Cholesterogenesis was 274 +/- 112 mg/d in controls and 641 +/- 201 mg/d in GSD-1a patients (p < 0.01). Plasma triglyceride-palmitate derived from de novo lipogenesis was 7.1 +/- 9.4 and 86.3 +/- 42.5 micromol/h in controls and patients, respectively (p < 0.01). Production of VLDL did not show a consistent difference between the groups, but conversion of VLDL into intermediate density lipoproteins was relatively retarded in all patients (0.6 +/- 0.5 pools/d) compared with controls (4.3 +/- 1.8 pools/d). Fractional catabolic rate of intermediate density lipoproteins was lower in patients (0.8 +/- 0.6 pools/d) compared with controls (3.1 +/- 1.5 pools/d). Whole body lipolysis was similar, i.e., 4.5 +/- 1.9 micromol/kg/min in patients and 3.8 +/- 1.9 micromol/kg/min in controls. Hyperlipidemia in GSD-1a is associated with strongly increased lipid production and a slower relative conversion of VLDL to LDL.

Safe and unsafe duration of fasting for children with MCAD deficiency.

OBJECTIVE: To study the safe and unsafe duration of fasting in children with medium chain acyl-Coenzyme A dehydrogenase (MCAD) deficiency, the literature and the database on Dutch MCAD-deficient patients were searched for data on fasting studies in patients with MCAD deficiency. MATERIALS AND METHODS: These data were extended with information on fasting studies performed on our patients with MCAD deficiency known in the Beatrix Children's Hospital, UMC Groningen, The Netherlands. The data reflect considerable inter-individual variation and overlap between safe and unsafe duration of fasting. RESULTS: In six out of 35 fasting tests, symptoms were reported before hypoglycaemia was observed. Until 1 year of age, the median safe and unsafe duration of fasting was 12 hours (n=7, range 8-19 hours) and 18 hours (n=5, range 15-20 hours), respectively. After the first year of life, the median safe and unsafe duration of fasting was 18 hours (n=17, range 10-24 hours) and 20 hours (n=9, range 13-32 hours), respectively. CONCLUSION: Therefore, to conclude, we recommend a maximum duration of fasting in children with MCAD deficiency of 8 hours between 6 months and 1 year of age, 10 hours in the second year of life and 12 hours thereafter. From this study, no conclusions can be drawn on the duration of fasting during situations of intercurrent illness, especially with fever.

Glycogen storage disease type I: diagnosis, management, clinical course and outcome. Results of the European Study on Glycogen Storage Disease Type I (ESGSD I).

UNLABELLED: Glycogen storage disease type I (GSD I) is a relatively rare metabolic disease and therefore, no metabolic centre has experience of large numbers of patients. To document outcome, to develop guidelines about (long-term) management and follow-up, and to develop therapeutic strategies, the collaborative European Study on GSD I (ESGSD I) was initiated. This paper is a descriptive analysis of data obtained from the retrospective part of the ESGSD I. Included were 231 GSD Ia and 57 GSD Ib patients. Median age of data collection was 10.4 years (range 0.4-45.4 years) for Ia and 7.1 years (0.4-30.6 years) for Ib patients. Data on dietary treatment, pharmacological treatment, and outcome including mental development, hyperlipidaemia and its complications, hyperuricaemia and its complications, bleeding tendency, anaemia, osteopenia, hepatomegaly, liver adenomas and carcinomas, progressive renal disease, height and adult height, pubertal development and bone maturation, school type, employment, and pregnancies are presented. Data on neutropenia, neutrophil dysfunction, infections, inflammatory bowel disease, and the use of granulocyte colony-stimulating factor are presented elsewhere (Visser et al. 2000, J Pediatr 137:187-191; Visser et al. 2002, Eur J Pediatr DOI 10.1007/s00431-002-1010-0). CONCLUSION: there is still wide variation in methods of dietary and pharmacological treatment of glycogen storage disease type I. Intensive dietary treatment will improve, but not correct completely, clinical and biochemical status and fewer patients will die as a direct consequence of acute metabolic derangement. With ageing, more and more complications will develop of which progressive renal disease and the complications related to liver adenomas are likely to be two major causes of morbidity and mortality.

Is glycogen storage disease 1a associated with atherosclerosis?

UNLABELLED: Deficiency of microsomal glucose-6-phosphatase in liver and kidney leads to glycogen storage disease type 1a (GSD 1a). Notwithstanding intensive dietary therapy, moderate to severe dyslipidaemia and microalbuminuria, both known atherosclerotic risk factors, remain present. Although more patients reach adult age, no information is still available about accelerated atherosclerosis. The aim of our study was to investigate whether GSD 1a was associated with premature atherosclerosis. In nine adolescent patients (mean age 22.7+/-3.4 years) and nine matched healthy control subjects, lipid profile, blood pressure, ankle-brachial indices, aortic distensibility and intima-media thickness (IMT) of the carotid and femoral arteries were determined. As expected, lipid profiles were significantly unfavourable in the patient group compared with the control group. No differences were found in blood pressure, ankle-brachial indices and aortic distensibility between both groups. IMT segments were comparable in both groups, with even thinner segments in the patient group. In different multivariate models, GSD 1a remained an independent predictor for a thinner IMT (R(2)=0.90; beta=-0.69; P=0.018). CONCLUSION: glycogen storage disease type 1a is not associated with premature atherosclerosis, despite the existence of longstanding dyslipidaemia and microalbuminuria.

Guidelines for management of glycogen storage disease type I - European Study on Glycogen Storage Disease Type I (ESGSD I).

UNLABELLED: Life-expectancy in glycogen storage disease type I (GSD I) has improved considerably. Its relative rarity implies that no metabolic centre has experience of large series of patients and experience with long-term management and follow-up at each centre is limited. There is wide variation in methods of dietary and pharmacological treatment. Based on the data of the European Study on Glycogen Storage Disease Type I, discussions within this study group, discussions with the participants of the international SHS-symposium 'Glycogen Storage Disease Type I and II: Recent Developments, Management and Outcome' (Fulda, Germany; 22-25th November 2000) and on data from the literature, guidelines are presented concerning: (1). diagnosis, prenatal diagnosis and carrier detection; (2). (biomedical) targets; (3). recommendations for dietary treatment; (4). recommendations for pharmacological treatment; (5). metabolic derangement/intercurrent infections/emergency treatment/preparation elective surgery; and (6). management of complications (directly) related to metabolic disturbances and complications which may develop with ageing and their follow-up. CONCLUSION: In this paper guidelines for the management of GSD I are presented.

Granulocyte colony-stimulating factor in glycogen storage disease type 1b. Results of the European Study on Glycogen Storage Disease Type 1.

UNLABELLED: Patients with glycogen storage disease type 1b (GSD-1b) have neutropenia and neutrophil dysfunction that predispose to frequent infections and inflammatory bowel disease (IBD), for which granulocyte colony-stimulating factor (GCSF) is given. To investigate the use and the value of GCSF treatment in GSD-1b, a retrospective registry of GSD-1 patients born between 1960 and 1995 in 12 European countries was established. Included were 57 GSD-1b patients. Unglycosylated GCSF was given to 18 patients, median age of starting therapy was 8 years, longest duration of therapy 7 years. Dose varied between 2-10 micro g/kg, with a frequency from daily to twice per week. Neutropenia (defined as an absolute neutrophil count <0.5 x 10(9)/l) was found in 49 patients. In untreated patients, a significant decrease of haemoglobin, platelet counts and leucocyte counts with increasing age ( P<0.032, P<0.04 and P<0.001 respectively) was noted, whereas neutrophil counts remained low but stable with increasing age. In nine patients who were treated longer than 1 year, median neutrophil counts increased significantly and simultaneously median leucocyte counts and platelet counts decreased significantly. In all patients treated, the number and severity of infections decreased and the severity of IBD improved subjectively. The most serious complication of GCSF treatment was marked splenomegaly (four patients). CONCLUSION: in this retrospective study a significant haematological effect was documented and a subjective improvement of infections and inflammatory bowel disease. In view of the uncertainty, prospective controlled trials seem warranted to clarify the indication for the use of granulocyte colony-stimulating factor in this disease.

Consensus guidelines for management of glycogen storage disease type 1b - European Study on Glycogen Storage Disease Type 1.

UNLABELLED: Life expectancy in glycogen storage disease type 1 (GSD-1) has improved considerably. Its relative rarity implies that no metabolic centre has experience of large series of patients and therefore experience with long-term management and follow-up at each centre is limited. There is wide variation in methods of dietary and pharmacological treatment. Based on data from the European Study on Glycogen Storage Disease Type 1, discussions within this study group together with those at the International SHS Symposium 'Glycogen Storage Disease Type I and II: Recent Developments, Management and Outcome', Fulda, Germany (2000) and on data from the literature, a series of guidelines were drawn up. CONCLUSION: the following guidelines for the management of patients with glycogen storage disease type 1b are in addition to those general guidelines for glycogen storage disease type 1 and address specific problems related to neutropenia and neutrophil dysfunction.

Apoptotic neutrophils in the circulation of patients with glycogen storage disease type 1b (GSD1b).

Glycogen storage disease type 1b (GSD1b) is a rare autosomal recessive disorder characterized by hypoglycemia, hepatomegaly, and growth retardation, and associated-for unknown reasons- with neutropenia and neutrophil dysfunction. In 5 GSD1b patients in whom nicotin-amide adenine dinucleotide phosphate-oxidase activity and chemotaxis were defective, we found that the majority of circulating granulocytes bound Annexin-V. The neutrophils showed signs of apoptosis with increased caspase activity, condensed nuclei, and perinuclear clustering of mitochondria to which the proapoptotic Bcl-2 member Bax had translocated already. Granulocyte colony-stimulating factor (G-CSF) addition to in vitro cultures did not rescue the GSD1b neutrophils from apoptosis as occurs with G-CSF-treated control neutrophils. Moreover, the 2 GSD1b patients on G-CSF treatment did not show significantly lower levels of apoptotic neutrophils in the bloodstream. Current understanding of neutrophil apoptosis and the accompanying functional demise suggests that GSD1b granulocytes are dysfunctional because they are apoptotic.

Increased lipogenesis and resistance of lipoproteins to oxidative modification in two patients with glycogen storage disease type 1a.

We describe 2 patients with glycogen storage disease type 1a and severe hyperlipidemia without premature atherosclerosis. Susceptibility of low-density lipoproteins to oxidation was decreased, possibly related to the ~40-fold increase in palmitate synthesis altering lipoprotein saturated fatty acid contents. These findings are potentially relevant for antihyperlipidemic treatment in patients with glycogen storage disease type 1a.