Joseph I. Wolfsdorf

ESPE/LWPES consensus statement on diabetic ketoacidosis in children and adolescents

Diabetic ketoacidosis (DKA) is the leading cause of morbidity and mortality in children with type 1 diabetes mellitus (TIDM). Mortality is predominantly related to the occurrence of cerebral oedema; only a minority of deaths in DKA are attributed to other causes. Cerebral oedema occurs in about 0.3–1% of all episodes of DKA, and its aetiology, pathophysiology, and ideal method of treatment are poorly understood. There is debate as to whether physicians treating DKA can prevent or predict the occurrence of cerebral oedema, and the appropriate site(s) for children with DKA to be managed. There is agreement that prevention of DKA and reduction of its incidence should be a goal in managing children with diabetes.

Subclinical Brain Swelling in Children during Treatment of Diabetic Ketoacidosis

Clinically apparent cerebral edema is a rare and often fatal complication of diabetic ketoacidosis. To determine whether subclinical brain swelling occurs more commonly, we obtained cranial CT scans in six children with diabetic ketoacidosis treated with fluid resuscitation and continuous low-dose insulin therapy. Control scans were obtained before hospital discharge. Compared with the scans during convalescence, the early scans of all six children showed a narrowing of the brains ventricular system, compatible with brain swelling. Average changes in diameter were 1.3 +/- 0.1 mm for the third ventricle and 3.7 +/- 0.8 mm for the lateral ventricles (P less than 0.01). In addition, a narrowing of the subarachnoid spaces was subjectively noted during a blind reading of the early scans. Although no single scan was overtly indicative of cerebral edema, the data suggest that subclinical brain swelling may be a common occurrence during treatment of diabetic ketoacidosis in children. Sequential CT scans of the brain may provide a means of evaluating modifications of standard therapy aimed at preventing cerebral edema.

Diabetic ketoacidosis in children and adolescents with diabetes

aDivision of Endocrinology, Children’s Hospital Boston, MA, USA; bSchool of Women’s and Children’s Health, University of New South Wales, Sydney, Australia; cUniversity of Toronto, The Hospital for Sick Children, Toronto, Canada; dDepartment of Paediatrics, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK; eDepartment of Paediatrics, John Radcliffe Hospital, Oxford, UK; fEndocrinology Service Department of Paediatric Medicine, KK Children’s Hospital, Singapore; gDivision of Endocrinology, Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL, USA; hDepartment of Pediatric Endocrinology, Children’s Hospital, University of Pittsburgh, PA, USA; iDepartment of Pediatrics, Uddevalla Hospital, Uddevalla, Sweden

Glycogen Storage Disease in Adults

Table 1 The glycogen storage diseases (GSD) include more than ten separate genetic defects that impair glycogen breakdown, primarily in liver or muscle or both. Even the types most frequently encountered (GSD-Ia and GSD-III) are uncommon, each with an incidence of approximately 1 in 100 000 births. Thus, no single institution has followed and reported on a large series of patients. The importance of several major complications was recognized only recently because only single cases were initially reported. Our study represents the largest number of adults with GSD-Ia and GSD-Ib to be included in one investigation and is the first to focus on clinical and social outcomes. Although two groups of investigators recently described the clinical course of patients with GSD in Europe and Israel, most of the patients studied were children [1, 2]. Relatively little information is available about adults with these diseases. We collected information on adults with GSD-Ia, GSD-Ib, and GSD-III in the United States and Canada in order to identify long-term complications that may be amenable to prevention and to determine the effect of the disease on education, employment, and family life. Table 1. SI Units Glycogen Storage Disease Types Ia, Ib, and III Glycogen storage disease type Ia results from deficient glucose-6-phosphatase activity in liver, kidney, and intestine [3]. Glucose-6-phosphatase is a single 35-kd protein [4]. When glucose-6-phosphatase activity is deficient, the liver is unable to hydrolyze glucose from glucose-6-phosphate that has been derived either from the metabolism of stored glycogen or from gluconeogenesis. Patients must depend on dietary carbohydrate to maintain euglycemia; during a fast of more than a few hours, the serum glucose concentration may decrease profoundly, and seizures are common in children. Mental retardation is uncommon, however, because the brain is protected by its ability to metabolize lactate that is present at high concentrations in the serum. Chronic hypoglycemia causes a sustained increase of counter-regulatory hormones, such as cortisol. In childhood, GSD-Ia typically results in poor growth and delayed puberty. Hyperuricemia occurs probably because ATP synthesis from ADP is driven by deamination of the AMP product to inosine that is subsequently metabolized to uric acid. Renal excretion of uric acid may also be decreased because lactate competes for the renal anion transporter. Fatty liver and hyperlipidemia result from the large influx of adipose-derived fatty acids into the liver in response to low insulin and high glucagon and cortisol concentrations. Anemia that is refractory to iron supplementation is believed to occur because of chronic disease. In untreated adults with GSD-Ia, the blood glucose decreases only to about 2.8 mmol/L (50 mg/dL) after an overnight fast. Symptomatic hypoglycemia is uncommon in untreated adults, but increases of counter-regulatory hormones probably persist. Adults with GSD-Ia have a high incidence of hepatic adenomas and focal segmental glomerulosclerosis [3, 5, 6]. The continuing abnormalities in counter-regulatory hormones, together with the hyperuricemia and hyperlipidemia, may be responsible for many of the complications observed in adult patients. Glycogen storage disease type Ib results from a deficiency of the glucose-6-phosphate translocase that transports glucose-6-phosphate into the lumen of the endoplasmic reticulum where it is hydrolyzed by glucose-6-phosphatase [3]. The translocase has not been purified. Without the translocase, glucose-6-phosphate cannot reach the hydrolytic enzyme; thus, patients with GSD-Ib are also unable to maintain euglycemia. The resulting metabolic consequences are identical in both forms of GSD-I. Because patients with GSD-Ib also have neutropenia and recurrent bacterial infections [3, 7], it seems likely that the glucose-6-phosphate translocase plays a role in normal neutrophil function. In GSD-III, glycogen debranching enzyme is deficient [3]. This enzyme is a 165-kd protein that contains two catalytic sites that are required for activity. The enzyme has been cloned and sequenced [8]. Normally, successive glucose residues are released from glycogen by glycogen phosphorylase until the glycogen chains are within four glucose residues of a branch point. The first catalytic activity of the debranching enzyme (oligo-1,4,-1,4-glucantransferase) transfers three of the remaining glucose residues to the terminus of another glucose chain. The second catalytic activity (amylo-1,6-glucosidase) then hydrolyzes the branch-point glucose residue. Three molecular subgroups of GSD-III have been well defined [9]; each is associated with enzyme deficiency in the liver and with childhood hypoglycemia. In adults with GSD-III, hypoglycemia is uncommon. As in GSD-I, poor growth may be prominent, but the growth rate increases before puberty, and adult height is normal [10]. Additionally, increases in transaminase levels provide evidence of hepatocellular damage, and liver biopsies show periportal fibrosis [10], perhaps related to the abnormal short-branched glycogen structure. In patients with subtype GSD-IIIb, enzyme activity and immunoreactive material are absent in liver but are present in muscle; these patients do not have a myopathy. Patients with GSD-IIIa (78% of cases) lack enzyme activity and lack immunoreactive material in liver and muscle. Patients with GSD-IIId (7% of cases) lack only the transferase activity but have normal immunoreactive material in liver and muscle. In patients with GSD-IIIa and IIId, muscle weakness may occur either in childhood or after the third decade. Cardiomyopathy is apparent only after age 30 years [9]. Treatment of Glycogen Storage Disease For only the past 10 to 15 years, children with GSD-Ia and GSD-Ib were treated with either intermittent uncooked cornstarch or a nocturnal glucose infusion given by intragastric tube. When euglycemia is maintained in this manner, growth and pubertal development are normal, and it is hoped that the late complications of GSD-I will be prevented. A high-protein diet was recommended for patients with GSD-III. Diet supplementation can increase the growth rate in children with GSD-III [11], but beneficial results on the myopathy have been less well documented. In this retrospective study of adults with GSD types Ia, Ib, and III, we found, in addition to complications frequently recognized, a high incidence of osteopenia and fractures and of nephrocalcinosis, kidney stones, and pyelonephritis. We describe the long-term outlook for adult patients with GSD who have not had optimal lifelong dietary glucose therapy. Methods Information on patients 18 years of age or older was obtained by contacting specialists in pediatric metabolism, endocrinology, gastroenterology, and genetics throughout the United States and Canada and by advertising through the Association for Glycogen Storage Diseases and The New England Journal of Medicine. No registries of patients with GSD are available. Information was included on living adult patients with GSD and patients who had died since 1967. Diagnosis of GSD had been confirmed by enzyme assay of each patient or of an affected sibling. Fifty-six physicians were individually contacted. Nineteen stated that they were not treating any adult patients with GSD. Thirteen physicians in private practice or at 1 of 12 medical centers filled out a detailed questionnaire or sent copies of clinic and hospital records that were reviewed by two of us. To obtain an estimate of how many patients might be missed by this survey, we reviewed records from a reference laboratory (Washington University) of 21 patients with GSD-Ia and of 21 patients with GSD-III who were diagnosed between 1955 and 1972. If still alive, these patients would now range in age from 18 to 64 years. Our study includes only 5 of these patients with GSD-I and 1 with GSD-III. Thus, this report incompletely represents North American patients with GSD who are currently older than 18 years of age. Clinical, radiographic, and laboratory findings at the latest visit were obtained, but data were not universally available for every item on the questionnaire. In analyzing each response, information was considered to be available only if specifically recorded; omission of information was not recorded as either a negative or a positive response. The presence of liver adenomas, nephrocalcinosis, or kidney stones was based on data from ultrasound or radiographic studies. The diagnosis of osteopenia was based on data from radiographic studies. The normal values for height were taken from the National Center for Health Statistics [12]. Normal values for serum chemistry tests [13] were used. Results Glycogen Storage Disease Type Ia Case Report Patient 1, a 43-year-old divorced father of one child, is a poultry farmer. A liver biopsy and enzymatic assay were obtained at 4 years of age because of poor growth, hypoglycemia without seizures, hepatomegaly, and frequent nosebleeds. Despite frequent meals, growth continued to be poor, puberty was delayed, and the final adult height of 168 cm was achieved after 20 years of age. Allopurinol was taken inconsistently after one of many gouty attacks beginning from 18 years of age. The patient did not complete high school. As an adult, he has smoked 2 to 4 packs of cigarettes per day. After divorcing in his 20s, he frequently skipped breakfast and failed to follow a recommended diet. Instead, his diet was high in fat and consisted primarily of foods that required little preparation, such as candy and sandwiches. He has always denied symptomatic hypoglycemia, although his serum glucose concentration after an overnight fast is about 2.8 mmol/L (50 mg/dL). Beginning in his mid-20s, he had recurrent episodes of flank pain and hematuria that were treated with antibiotics, and he passed kidney stones. At age 24, an intravenous pyelogram showed punctate calcificati

Family environment and glycemic control: a four-year prospective study of children and adolescents with insulin-dependent diabetes mellitus.

&NA; An onset cohort of children and adolescents with insulin‐dependent diabetes mellitus (IDDM) and their parents were studied. Aspects of family environment were evaluated at study inception, and their influence on the initial level of, and change in, glycemic control over 4 years was examined. Family measures of expressiveness, cohesiveness, and conflict were linked to differences in the longitudinal pattern of glycemic control. In particular, the encouragement to act openly and express feelings directly (expressiveness) seemed to ameliorate deterioration of glycemic control over time in both boys and girls. Boys were especially sensitive to variations in family cohesiveness and conflict; those from more cohesive and less conflicted families showed less deterioration in glycemic control. This study demonstrated the important influence of family psychosocial factors present at diabetes onset on glycemic control in children and adolescents over the first 4 years of IDDM.

Diabetic Ketoacidosis in Infants, Children, and Adolescents

The adage “A child is not a miniature adult” is most appropriate when considering diabetic ketoacidosis (DKA). The fundamental pathophysiology of this potentially life-threatening complication is the same as in adults. However, the child differs from the adult in a number of characteristics. 1 ) The younger the child, the more difficult it is to obtain the classical history of polyuria, polydipsia, and weight loss. Infants and toddlers in DKA may be misdiagnosed as having pneumonia, reactive airways disease (asthma), or bronchiolitis and therefore treated with glucocorticoids and/or sympathomimetic agents that only compound and exacerbate the metabolic derangements. Because the diagnosis of diabetes is not suspected as it evolves, the duration of symptoms may be longer, leading to more severe dehydration and acidosis and ultimately to obtundation and coma. Even in developed countries, some 15–70% of all newly diagnosed infants and children with diabetes present with DKA (1–8). Generally, the rates of DKA are inversely proportional to rates of diabetes in that community, but throughout the U.S., the overall rates of DKA at diagnosis have remained fairly constant at ∼25% (6). DKA, defined by blood bicarbonate 14 years but did not differ significantly by sex or ethnicity (6). 2 ) The higher basal metabolic rate and large surface area relative to total body mass in children requires greater precision in delivering fluids and electrolytes. The degree of dehydration is expressed as a function of body weight, i.e., 10% dehydration implies 10% loss of total body weight as water. However, the calculation of basal requirements, although a constant per unit …

Concentration of Insulin Autoantibodies at Onset of Type I Diabetes: Inverse Log-Linear Correlation With Age

thin needle is no more difficult or painful than subcutaneous injection. Hence an intramuscular injection can be recommended (as part of an intensive educational program) to be performed when a more rapid insulin action is desired, e.g., before eating quickly absorbed carbohydrates, or in case of ketoacidotic deterioration. Depending on the thickness of the subcutaneous fat tissue layer, length of the needle, and injection technique used, the absorption of insulin in the deltoid area may follow the intramuscular route and its pharmacokinetics and biological action can thus be manipulated.

Psychological Adjustment to IDDM: 10-Year Follow-Up of an Onset Cohort of Child and Adolescent Patients

OBJECTIVE To evaluate the psychological adjustment of young adults with IDDM in comparison with similarly aged individuals without chronic illness. RESEARCH DESIGN AND METHODS An onset cohort of young adults (n = 57), ages 19–26 years, who have been followed over a 10-year period since diagnosis, was compared with a similarly aged group of young adults identified at the time of a moderately severe, acute illness (n = 54) and followed over the same 10-year period. The groups were assessed at 10-year follow-up in terms of 1) sociodemographic indices (e.g., schooling, employment, delinquent activities, drug use), 2) psychiatric symptoms, and 3) perceived competence. In addition, IDDM patients were examined for longitudinal change in adjustment to diabetes. RESULTS The groups differed only minimally in terms of sociodemographic indices, with similar rates of high school graduation, post-high school education, employment, and drug use. The IDDM group reported fewer criminal convictions and fewer non-diabetes-related illness episodes than the comparison group. There were no differences in psychiatric symptoms. However, IDDM patients reported lower perceived competence, with specific differences found on the global self-worth, sociability, physical appearance, being an adequate provider, and humor subscales. The IDDM patients reported improving adjustment to their diabetes over the course of the 10-year follow-up. CONCLUSIONS Overall, the young adults with IDDM appeared to be as psychologically well adjusted as the young adults without a chronic illness. There were, however, indications of lower self-esteem in the IDDM patients that could either portend or predispose them to risk for future depression or other difficulties in adaptation.

Diabetic ketoacidosis and hyperglycemic hyperosmolar state

aDivision of Endocrinology, Boston Children’s Hospital, Boston, MA, USA; bBarts Health NHS Trust, Royal London Hospital, London, UK; cInstitute of Endocrinology and Diabetes, The Children’s Hospital at Westmead; School of Women’s and Children’s Health, University of New South Wales, Sydney, Australia; dOxfordshire Children’s Diabetes Service, Oxford Children’s Hospital, Oxford, UK; eSection of Endocrinology, University of California, Davis School of Medicine, Sacramento, CA, USA; fPediatric Endocrinology Division, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India; gEndocrinology Service, Department of Paediatrics, KK Women’s and Children’s Hospital, Singapore; hDepartment of Paediatrics and Child Health, University of Nairobi, Nairobi, Kenya ; iDepartment of Pediatrics, University of Florida College of Medicine, Gainesville, FL, USA; jDivision of Endocrinology, Diabetes and Metabolism, Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA and kDepartment of Pediatrics, NU Hospital Group, Uddevalla and Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden

Glycogen storage diseases.

Joseph I. Wolfsdorf1 and David A. Weinstein2 1Senior Associate in Medicine, Director, Diabetes Program, Division of Endocrinology; Chief, Charles A. Janeway Medical Firm, Children’s Hospital Boston; Associate Professor of Pediatrics, Harvard Medical School, Boston 02115, MA, USA; 2Assistant in Medicine (Endocrinology), Children’s Hospital Boston; Instructor in Pediatrics, Harvard Medical School, Boston, MA, USA