Maintenance Treatment With Low‐Dose Mercaptopurine in Combination With Allopurinol in Children With Acute Lymphoblastic Leukemia and Mercaptopurine‐Induced Pancreatitis

Mercaptopurine (6‐mercaptopurine, 6MP) is a mainstay of curative therapy in childhood acute lymphoblastic leukemia (ALL), and contributes to its 90% overall survival rate. We present two patients with ALL who suffered with severe pancreatitis secondary to 6MP. Through the use of allopurinol in conjunction with reduced dose 6MP, we were able to continue 6MP without further pancreatitis. This report contributes to the small body of literature on 6MP associated pancreatitis in childhood ALL and describes a novel approach to continued use of 6MP during therapy.     

How low is too low? Use of cluster analysis to define low levels of mercaptopurine metabolites

BACKGROUND: To group patients receiving treatment for acute lymphoblastic leukemia (ALL) according to their oral mercaptopurine (6-MP) metabolite levels and to establish cut-off points to screen for potential poor clinical outcome. PROCEDURE: Methodological study using 6-MP metabolite levels from 48 adolescent ALL patients enrolled in a multicenter adherence study. Cluster analysis was the primary analytical technique. We used two validation methods (a split-sampling and a simulation technique) for validating the results. RESULTS: Four clusters were retained in our initial analysis using our first group of patients (n = 27). Three clusters (labeled 1, 2, and 4) exhibited the expected negative correlation between the two metabolites, that is, "high" values of one were associated with "low" values of the other. One cluster (labeled 3) had "low" levels for both TGN and MMP. Five of the 27 adolescents had their 6-MP "held" during the study. Post-hoc examination of the results revealed that all five grouped in Cluster 3 during the time that their medications were stopped, but grouped in other clusters at other times. The median ANC was highest in Cluster 3, consistent with low therapeutic drug levels. Parameters were reproducible with both validation methods. Values below the respective 75th centile for both TGN and MMP in Cluster 3 for the complete sample (n = 48) are suggested as representing a potentially higher risk for relapse. CONCLUSIONS: This study provides an objective method for identifying patients at risk for treatment failure due to suboptimal 6-MP therapy; the clinical significance of this approach should be examined in future studies.     

Predictors of mobile telephone use and exposure analysis in Australian adolescents

Aim: Australian adolescents are increasingly using mobile telephones (MP) while the debate on MP safety persists. This group is not generally engaged in full‐time employment, suggesting that their MP use is not work related. We investigated possible predictors of MP use in young people. Methods: We assessed exposure to radiofrequency energy from MP by means of a self‐administered questionnaire adapted from INTERPHONE – an international case‐control study of adult brain, head and neck tumours. We investigated possible determinants of MP use in adolescent Australians using self‐reported number of incoming and outgoing voice calls as exposure metric. Results: There is a high prevalence of MP use amongst Australian adolescents (94%). Males were significantly younger than females at age of first uptake of MP (P= 0.02). Participants without siblings were significantly younger at age of first uptake. Personality traits were associated with regular MP usage: higher psychoticism scores were associated with regular use (IRR = 1.06, P= 0.03); there was a tendency for students with higher extraversion scores to report more MP use. Parental socio‐economic status was associated with MP use, but parents who expressed moderate/high level concerns about possible health risks of use were more likely to have children who used MP (OR = 4.06, P= 0.05). Conclusions: Almost all adolescent Australians use MP, but regular exposure was associated with personality traits. Parental socio‐economic status and perceived health risks of MP use were also associated with use of phones. Longitudinal studies are needed to assess the predictors of mobile phone use in the long term.     

Primary renal neuroblastoma with metastasis and matrix metalloproteinase‐14 expression

We herein report the rare case of a 4‐year–5‐month‐old boy who presented with primary renal neuroblastoma. The patient developed repeated lung and liver metastatic recurrences, but, following a combination of chemotherapy, radiation therapy and aggressive surgical resection, the patient is now in remission. To investigate the pathogenesis of lung metastasis, immunohistochemistry was performed for matrix metalloproteinase‐9 and ‐14 (MMP‐9 and MMP‐14), molecular markers of invasion, metastasis and angiogenesis in neuroblastoma. In the present case, MMP‐9 expression was not observed, but MMP‐14 expression was detected in the primary lesion and was more highly expressed in the metastatic lesion compared with the primary one. Given the MMP‐14 staining in other cases, expression of MMP‐14 may be associated with the aggressiveness of the tumor. This suggests that selected clones with high MMP‐14 expression in the primary tumor might metastasize and form MMP‐14‐rich lesions.     

Response to mercaptopurine for refractory autoimmune cytopenias in children

Background

Several treatment strategies are available for children with severe immune thrombocytopenic purpura (ITP) and other immune cytopenias refractory to initial therapies. 6‐Mercaptopurine (6MP) is one option, however it has not been well studied in children, especially as a single agent, and no pediatric case series have been reported since 1970.

Patients and Methods

We reviewed the experience at our institution over 8 years, using 6MP as a steroid sparing treatment for children with ITP, auto‐immune hemolytic anemia (AIHA) or Evans syndrome. A total of 29 pediatric patients were treated with 6MP from 2000 to 2007.

Results

Response was defined as a rise in hemoglobin by at least 1.5 g/dl and to a level of 10 g/dl or greater in patients treated for anemia, or a platelet count ≥50 × 10⁹/L in patients treated for thrombocytopenia. We found an overall response rate of 83% among all patients. Fourteen percent of patients stopped drug because of side effects.

Conclusions

These results suggest that 6MP can be an effective single‐agent treatment for refractory immune cytopenias in children. Prospective studies are warranted to determine long‐term efficacy and toxicity and to more clearly define patient populations most likely to respond. Pediatr Blood Cancer 2009;52:80–84. © 2008 Wiley‐Liss, Inc.     

不同表现肺炎支原体肺炎患儿血浆白细胞介素-6、8和18水平变化的意义

目的探讨不同临床表现的肺炎支原体(MP)肺炎患儿血浆IL-6、8和18水平变化的意义。方法根据患儿发热和肺部炎症转归时间,分为普通组(21例)和迁延组(8例);利用酶联免疫吸附试验检测MP肺炎患儿和对照组(10例)儿童血浆IL-6、8和18水平,并进行统计学比较。结果MP肺炎急性期普通组和迁延组血浆IL-6、8和18水平均明显升高,与对照组比较差异均有显著性(P均<0.05);恢复期普通组和迁延组血浆IL-6和IL-8水平下降,与对照组比较无显著意义(P>0.05);但迁延组IL-18水平恢复期虽有下降,但仍较对照组高,且差异具有显著意义(P<0.05),而普通组IL-18水平则恢复正常,与对照组比较差异无显著性(P>0.05)。结论IL-6、8和18均可能参与MP肺炎的发病机制;IL-18可能与疾病迁延有关,且迁延型MP肺炎可能为自身免疫性疾病。     

Symptomatic hypoglycemia: an unusual side effect of oral purine analogues for treatment of ALL

Symptomatic hypoglycemia is an unusual complication in children receiving oral purine analogues for treatment of childhood acute lymphoblastic leukemia (ALL). The exact mechanism of the hypoglycemic effect of the antimetabolic therapy remains unclear. Reduced hepatic glycogen stores or impaired hepatic glyconeogenesis may partly explain the hypoglycemia. To prevent hypoglycemia, food containing complex carbohydrates is recommended before sleep. In severe cases of hypoglycemia due to 6-mercaptopurine (6-MP), the dose can be given in the morning and if this fails 6-MP can be discontinued for a short period of time. We report a 3-year-old child who developed severe early morning hypoglycemia episodes that resolved after decreasing 6-MP while receiving non-high risk ALL therapy.     

Intravenous glucagon in a deliberate insulin overdose in an adolescent with type 1 diabetes mellitus

Massive insulin overdose may be associated with unpredictable and prolonged hypoglycemia. Concerns surrounding the potential provocation of insulin release from beta cells have previously prevented the use of intravenous glucagon as an adjunct to infusion of dextrose in this situation. We describe the case of a 15‐yr‐old boy with type 1 diabetes mellitus (T1DM) who presented with profound hypoglycemia following an overdose of an unknown quantity of premixed insulin. Owing to an increasing dextrose requirement and a dependence on hourly intramuscular glucagon injections, a continuous intravenous infusion of glucagon was commenced which successfully avoided the requirement for central venous access or concentrated dextrose infusion. Nausea was managed with anti‐emetics. Intramuscular and subcutaneous glucagon is effective in the management of refractory and severe hypoglycemia in youth with both T1DM and hyperinsulinism. Concerns regarding the precipitation of rebound hypoglycemia with the use of intravenous glucagon do not relate to those with T1DM. This treatment option may be a useful adjunct in the management of insulin overdose in youth with T1DM and may avoid the requirement for invasive central venous access placement.     

Hypoglycemia,S‐ACE and ACE genotypes in a Danish nationwide population of children and adolescents with type 1 diabetes

Johannesen J, Svensson J, Bergholdt R, Eising S, Gramstrup H, Frandsen E, Dick‐Nielsen J, Hansen L, Pociot F, Mortensen HB, The Danish Society for Diabetes in Childhood and Adolescence. Hypoglycemia, S‐ACE and ACE genotypes in a Danish nationwide population of children and adolescents with type 1 diabetes. Objective: High S‐ACE levels have been shown to predispose to increased risk of hypoglycemia, however; some inconsistency relates to the risk of the ACE genotype. We investigated the association between S‐ACE level at diagnosis and ACE genotype to long‐term risk of severe hypoglycemia in more than 1000 children and adolescents with type 1 diabetes being part of the Danish Registry of Childhood diabetes over a 10‐yr period. Research design and methods: The Registry provided annual registration of clinical data, e.g., HbA1c, blood glucose monitoring, insulin type and dosage and acute diabetic complications (hypoglycemia and DKA). A BioBank coupled to the Registry comprised serum for measuring S‐ACE levels and DNA for ACE genotyping. Results: A total of 1037 individuals were included, aged 9.97 yr (SD 3.84). A total of 622 severe hypoglycemic episodes were observed in 270 individuals. Associations to increased risk of hypoglycemia generated from a negative binominal model were long diabetes duration (p < 0.0001) and high S‐ACE level (p = 0.0497) when adjusted for ACE genotype. In the stratified analysis, S‐ACE and insulin dosage were associated with hypoglycemia in girls (p = 0.026 and 0.028, respectively). An association of S‐ACE level to ACE genotype was identified; however, no difference in the frequency of hypoglycemia, diabetes duration or HbA1c was demonstrated between ACE genotypes. Conclusion: This large nationwide cohort has identified an increased risk for hypoglycemia associated with higher S‐ACE level, however only in girls. A strong association was found between ACE genotype and S‐ACE levels, but ACE genotype was not related to risk of hypoglycemia.     

The Scylla and Charybdis of glucose control in childhood type 1 diabetes?

Glucose control in childhood type 1 diabetes is difficult and often characterized by significant glucose variability, including periods of prolonged hyperglycemia and intermittent episodes of hypoglycemia that can be severe. The brain of the developing child is thought to be more susceptible to metabolic insults because of its relatively high demand for glucose to fuel neuronal growth and differentiation. In this review we consider the impact of glucose variability, especially when associated with recurrent hypoglycemia, on long‐term cognitive function in childhood type 1 diabetes. At present, this indicates a subtle effect of type 1 diabetes per se on a number of cognitive modalities. Within the population of children with type 1 diabetes, a history of severe hypoglycemia also appears to have an additional negative effect on cognitive function. However, interpretation of the literature is difficult in that the human studies draw largely from cross‐sectional observational epidemiology while more basic work has used models that do not translate well into human disease. Moreover, it is likely to be many years before we will be able to clearly document the effects of recurrent hypoglycemia or chronic hyperglycemia on cognitive function. In the meantime, it seems appropriate to advocate that minimizing glucose variability when achieving glycemic targets should be the therapeutic goal of clinicians involved in the management of childhood type 1 diabetes.     

Hyperglycemia not hypoglycemia alters neuronal dendrites and impairs spatial memory

Background/Objective: We previously reported that chronic hyperglycemia, but not hypoglycemia, was associated with the reduction of neuronal size in the rat brain. We hypothesized that hyperglycemia‐induced changes in neuronal structure would have negative consequences, such as impaired learning and memory. We therefore assessed the effects of hyperglycemia and hypoglycemia on neuronal dendritic structure and cognitive functioning in young rats. Design/Methods: Experimental manipulations were conducted on male Wistar rats for 8 wk, beginning at 4 wk of age. At the completion of the treatments, all rats were trained in the radial‐arm water maze, a spatial (hippocampus‐dependent) learning and memory task. Three groups of rats were tested: an untreated control group, a streptozotocin‐induced diabetic (STZ‐D) group, and an intermittent hypoglycemic group. Following behavioral training, the brains of all animals were examined with histologic and biochemical measurements. Results: Peripheral hyperglycemia was associated with significant increases in brain sorbitol (7.5 ± 1.6 vs. 5.84 ± 1.0 μM/mg) and inositol (9.6 ± 1.4 vs. 7.1 ± 1.1 μM/mg) and reduced taurine (0.65 ± 0.1 vs. 1.3 ± 0.1 mg/mg). Histologic evaluation revealed neurons with reduced dendritic branching and spine density in STZ‐D rats but not in control or hypoglycemic animals. In addition, the STZ‐D group exhibited impaired performance on the water maze memory test. Conclusions: Hyperglycemia, but not hypoglycemia, was associated with adverse effects on the brain polyol pathway activity, neuronal structural changes, and impaired long‐term spatial memory. This finding suggests that the hyperglycemic component of diabetes mellitus has a greater adverse effect on brain functioning than does intermittent hypoglycemia.     

Glycemic variability in preterm infants receiving intermittent gastric tube feeding: Report of three cases

Late‐onset hypoglycemia (day 12–16, blood glucose <50 mg/dL) was detected in three preterm infants (birthweight 998–1780 g; gestational age 27–30 weeks) by routine screening. All infants showed high serum insulin levels and extremely low ketone levels at the time of hypoglycemia. Continuous glucose monitoring was conducted at 31–34 weeks' postconceptual age when the infants were receiving intermittent gastric tube feeding with no intravenous glucose infusion. The continuous glucose monitoring results showed characteristic postprandial glucose increases and subsequent sharp deceases along with many hyper‐ and hypoglycemic events. This fluctuating pattern disappeared at 38–40 weeks' postconceptual age. These observations suggest that prolonged insulin oversecretion may be associated with early aggressive intravenous nutrition, and that large glycemic variability is a common feature of tube‐fed preterm infants that can be explained by immature glucose homeostasis.     

Portosystemic shunt as a cause of congenital hyperinsulinemic hypoglycemia

Congenital hyperinsulinemic hypoglycemia (CHH) is characterized by the inappropriate secretion of insulin from pancreatic beta cells in the presence of hypoglycemia. We herein describe the case of a 5‐month‐old boy with CHH due to congenital portosystemic shunt (CPSS). Insulin secreted from pancreatic beta cells flows into the portal vein and is first metabolized in the liver. First‐pass elimination of insulin in the liver leads to great decrease in insulin concentration by approximately 40–80% in humans. CPSS accounts for a large quantity of insulin delivery into the systemic circulation due to the lack of hepatic first‐pass elimination. Hypoglycemia can result from consistently high levels of insulin after reaching normal glucose level. CPSS therefore should be considered as a rare cause of CHH, especially in the case of post‐prandial hyperinsulinemic hypoglycemia.     

Severe hypoglycemia secondary to methimazole‐induced insulin autoimmune syndrome in a 16 year old African‐American male

Insulin autoimmune syndrome (IAS) or Hirata's disease is a rare disorder characterized by hypoglycemia secondary to insulin autoantibodies (IAb). Over 200 patients have been described from Japan with significantly less numbers being reported from outside the Orient. IAS is more common in patients older than 40 yr of age with reports in the pediatric age group being notably rarer. Exposure to sulfhydryl group containing medications is implicated in the pathogenesis of this syndrome. In this report, we describe a case of IAS in an African‐American adolescent. A 16‐yr‐old healthy African‐American male was diagnosed with Graves' disease and started on Methimazole. Four weeks later, he was found unconscious and hypoglycemic (blood sugar 1.5 mmol/L). Evaluation was negative for insulinoma. Insulin antibodies were positive. Oral glucose tolerance test revealed elevated free insulin concentrations with disproportionately elevated total insulin levels. The patient was started on prednisone, diazoxide, and propranolol for management of IAS and hyperthyroidism. Thyroid radio‐ablation was subsequently undertaken. The doses of prednisone and diazoxide were tapered and these medications discontinued after 9 months. The insulin antibody levels decreased gradually and became undetectable in 6 months with resolution of the hypoglycemia.     

Severe fasting hypoglycemia in a child after total pancreatectomy with islet autotransplantation

TPIAT is an increasingly utilized treatment option for select children with CP. Post‐TPIAT fasting hypoglycemia, unrelated to exogenous insulin, is a complication recently reported in adults. This phenomenon has not been described in children. We review a case of severe fasting hypoglycemia in an adolescent female occurring 10 months post‐TPIAT. A 12‐year‐old girl underwent TPIAT for CP. Ten months postoperatively she developed recurrent hypoglycemia on a total daily insulin dose of 0.03 units/kg. Consequently, insulin therapy was discontinued. Approximately 20 hours after her last rapid‐acting insulin exposure, she had an episode of fasting hypoglycemia (33 mg/dL on glucometer). Her CGM documented two separate, precipitous drops in glucose overnight. The family was instructed to revise her diet, and there were no subsequent episodes of severe, fasting hypoglycemia. This is the first report of fasting hypoglycemia occurring post‐TPIAT in a pediatric patient. Use of a CGM allowed for documentation of glucose trends and alarm notification of hypoglycemic events. Dietary changes appeared to help mitigate hypoglycemia recurrence. This report demonstrates that fasting hypoglycemia is a potential complication that should be recognized and safeguarded against in post‐TPIAT pediatric patients.     

Unusual skin rash following withdrawal of oral 6-mercaptopurine in children with leukemia

Sixteen episodes of a distinctive, papular rash occurred in eight patients following withdrawal of 6-mercaptopurine (6MP) and methotrexate (MTX) used as maintenance therapy for acute lymphoblastic leukemia (ALL). The rash also developed in one of the eight patients when only 6MP was discontinued. The eruption occurred mainly on the face, and in this site resembled the perioral dermatitis seen following withdrawal of topical fluorinated steroids. The rash generally began within 3 weeks of stopping 6MP and lasted 3 to 4 weeks. It failed to improve with the use of topical corticosteroid. We conclude that this rash is caused by the withdrawal of oral 6MP.     

Perceived family burden and emotional distress: similarities and differences between mothers and fathers of children with type 1 diabetes in a population‐based study

Haugstvedt A, Wentzel‐Larsen T, Rokne B, Graue M. Perceived family burden and emotional distress: similarities and differences between mothers and fathers of children with type 1 diabetes in a population‐based study. Background: Parenting children with diabetes entail an extra burden for the families. More information is needed about associations between perceived family burden and emotional distress in both mothers and fathers. Objective: To analyze (i) perceived burden and emotional distress in mothers and fathers of children with type 1 diabetes and (ii) associations between parental burden and distress and factors related to the child. Methods: Mothers (n = 103) and fathers (n = 97) of 115 children (1–15 yr) with type 1 diabetes participated in this population‐based survey. The parents completed the Hopkins Symptom Checklist‐25 items (HSCL‐25), measuring emotional distress, and the Family Burden Scale, which includes five questions measuring perceived family burden related to the child's diabetes. Results: Both mothers and fathers reported that the greatest burden was related to long‐term health concerns. The mothers reported a significantly greater burden related to medical treatment and significantly more emotional distress than the fathers. The mothers' perceived burden was significantly correlated with emotional distress. Nighttime blood glucose measurements were significantly associated with perceived parental burden, and experienced nocturnal hypoglycemia was significantly associated with parental emotional distress. Conclusions: The higher perceived burden related to medical treatment, the more emotional distress, and the correlations between burdens and emotional distress in mothers vs. fathers emphasize the importance of discussing both parents' roles and responsibilities in relation to the child's diabetes in follow‐up. In the consultations, emphasizing nighttime caregiving and nocturnal hypoglycemia might also be important to prevent emotional distress.     

Celiac disease in children and adolescents with type I diabetes: importance of hypoglycemia

BACKGROUND: Symptomatic hypoglycemia is an unavoidable problem in the treatment of type I diabetes. Celiac disease is associated with malabsorption and may therefore represent an important risk factor. METHODS: The frequency of symptomatic hypoglycemia in patients with type I diabetes and celiac disease (cases) was compared with those of patients who had diabetes without celiac disease (controls). For this purpose, each case was matched for age, sex, and duration of disease with one to two control patients. Indices of metabolic control (hemoglobin [Hb]A1c, frequency of hypoglycemia, and total insulin requirement) were retrieved for the 18 months before and after diagnosis of celiac disease. RESULTS: Eighteen patients (6 males and 12 females) had diagnosed celiac disease and were matched with 26 control patients (10 males and 16 females). There was no difference in age (11.0 years; range, 1.8-21.9 vs. 13.1 years; range, 2.3-22; P = 0.3) and duration of disease (8.4 years; range, 1.2-19.3 vs. 8.3 years; range, 1.1-18.7; P = 0.3) between the two groups. During the 6 months before and after diagnosis of celiac disease the cases had significantly more hypoglycemic episodes than the controls (means +/- SD; 4.5+/-4 vs. 2.0+/-2.2 episodes/months, P = 0.01). This was reflected by a progressive reduction in insulin requirement over the 12 months before diagnosis reaching a nadir at time 0 (0.6+/-0.2 vs. 0.9+/-0.3, P = 0.05). CONCLUSION: These data suggest that underlying celiac disease is associated with an increased risk of symptomatic hypoglycemia and that the introduction of a gluten-free diet with normalization of the intestinal mucosa may reduce its frequency.     

Diagnostic procedures in pediatric hypoglycemias

Depending on its etiology hypoglycemia appears after short or prolonged periods of fasting and shows different metabolite and hormonal patterns. In children it is caused by a disturbed homoeostasis of blood glucose (hormonal disorders, decreased activity of glycogenolysis or gluconeogenesis), by a primarily decreased ketogenic activity, or by a deranged adjustment of ketogenesis and carbohydrate metabolism. For the diagnostic procedure the age at manifestation, periods of fasting as well as signs and symptoms (f.e. hepatomegaly, growth retardation, somnolence) have to be carefully evaluated. Based on the extent of ketonemia the hypoglycemic syndromes can be classified into ketotic and hypoketotic forms. Hyperinsulinism, defects in fatty acid oxydation, glycogen storage disease I and postprandial hypoglycemias belong to the second category. In diagnosing hypoglycemia analysis of metabolite (glucose, lactate, beta-hydroxybutyrate, free fatty acids, carnitine) and hormonal (insulin, cortisol, growth hormone) patterns during hypoglycemic episodes is of outstanding importance. Urine has to be analysed for abnormal organic acids in order to demonstrate disturbed fatty acid oxydation. Rarely, loading tests with intermediates of carbohydrate metabolism are necessary. Suspected enzyme deficiencies have to be demonstrated in appropriate tissues (liver biopsy, erythrocytes, fibroblasts).