David A. Weinstein

Hepatocellular carcinoma in glycogen storage disease type Ia: a case series.

SummaryWe present a series of 8 patients (6 males, 2 females) with hepatocellular carcinoma (HCC) and glycogen storage disease type Ia (GSD Ia). In this group, the age at which treatment was initiated ranged from birth to 39 years (mean 9.9 years). All patients but one were noncompliant with treatment. Hepatic masses were first detected at an age range of 13–45 years (mean 28.1 years). Age at diagnosis of HCC ranged from 19 to 49 years (mean 36.9 years). Duration between the diagnosis of liver adenomas and the diagnosis of HCC ranged from 0 to 28 years (mean 8.8 years, SD=11.5). Two patients had positive hepatitis serologies (one hepatitis B, one hepatitis C). α-Fetoprotein (AFP) was normal in 6 of the 8 patients. Carcinoembryonic antigen (CEA) was normal in the 5 patients in which it was measured. Current guidelines recommend abdominal ultrasonography with AFP and CEA levels every 3 months once patients develop hepatic lesions. Abdominal CT or MRI is advised when the lesions are large or poorly defined or are growing larger. We question the reliability of AFP and CEA as markers for HCC in GSD Ia. Aggressive interventional management of masses with rapid growth or poorly defined margins may be necessary to prevent the development of HCC in this patient population.

Urinary hepcidin in congenital chronic anemias.

Hepcidin, a regulator for iron homeostasis, is induced by inflammation and iron burden and suppressed by anemia and hypoxia. This study was conducted to determine the hepcidin levels in patients with congenital chronic anemias.

Impaired Intestinal Iron Absorption in Crohn’s Disease Correlates with Disease Activity and Markers of Inflammation

Background Anemia in patients with Crohns disease (CD) is a common problem of multifactorial origin, including blood loss, malabsorption of iron, and anemia of inflammation. Anemia of inflammation is caused by the effects of inflammatory cytokines [predominantly interleukin‐6 (IL‐6)] on iron transport in enterocytes and macrophages. We sought to elucidate alterations in iron absorption in pediatric patients with active and inactive CD. Methods Nineteen subjects with CD (8 female, 11 male patients) were recruited between April 2003 and June 2004. After an overnight fast, serum iron and hemoglobin levels, serum markers of inflammation [IL‐6, C‐reactive protein (CRP), and erythrocyte sedimentation rate], and a urine sample for hepcidin assay were obtained at 8 am. Ferrous sulfate (1 mg/kg) was administered orally, followed by determination of serum iron concentrations hourly for 4 hours after the ingestion of iron. An area under the curve for iron absorption was calculated for each patient data set. Results There was a strong inverse correlation between the area under the curve and IL‐6 (P = 0.002) and area under the curve and CRP levels (P = 0.04). Similarly, the difference between baseline and 2‐hour serum iron level (&Dgr;[Fe]2hr) correlated with IL‐6 (P = 0.008) and CRP (P = 0.045). When cutoff values for IL‐6 (>5 pg/mL) and CRP (>1.0 mg/dL) were used, urine hepcidin levels also positively correlated with IL‐6 and CRP levels (P = 0.003 and 0.007, respectively). Conclusions Subjects with active CD have impaired oral iron absorption and elevated IL‐6 levels compared with subjects with inactive disease. These findings suggest that oral iron may be of limited benefit to these patients. Future study is needed to define the molecular basis for impaired iron absorption.

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

Glycogen Storage Disease Type III diagnosis and management guidelines

Purpose: Glycogen storage disease type III is a rare disease of variable clinical severity affecting primarily the liver, heart, and skeletal muscle. It is caused by deficient activity of glycogen debranching enzyme, which is a key enzyme in glycogen degradation. Glycogen storage disease type III manifests a wide clinical spectrum. Individuals with glycogen storage disease type III present with hepatomegaly, hypoglycemia, hyperlipidemia, and growth retardation. Those with type IIIa have symptoms related to liver disease and progressive muscle (cardiac and skeletal) involvement that varies in age of onset, rate of disease progression, and severity. Those with type IIIb primarily have symptoms related to liver disease. This guideline for the management of glycogen storage disease type III was developed as an educational resource for health care providers to facilitate prompt and accurate diagnosis and appropriate management of patients.Methods: An international group of experts in various aspects of glycogen storage disease type III met to review the evidence base from the scientific literature and provided their expert opinions. Consensus was developed in each area of diagnosis, treatment, and management.Results: This management guideline specifically addresses evaluation and diagnosis across multiple organ systems (cardiovascular, gastrointestinal/nutrition, hepatic, musculoskeletal, and neuromuscular) involved in glycogen storage disease type III. Conditions to consider in a differential diagnosis stemming from presenting features and diagnostic algorithms are discussed. Aspects of diagnostic evaluation and nutritional and medical management, including care coordination, genetic counseling, hepatic transplantation, and prenatal diagnosis, are addressed.Conclusions: A guideline that will facilitate the accurate diagnosis and appropriate management of individuals with glycogen storage disease type III was developed. This guideline will help health care providers recognize patients with all forms of glycogen storage disease type III, expedite diagnosis, and minimize stress and negative sequelae from delayed diagnosis and inappropriate management. It will also help identify gaps in scientific knowledge that exist today and suggest future studies.

Recommendations from the Pediatric Endocrine Society for Evaluation and Management of Persistent Hypoglycemia in Neonates, Infants, and Children

Recommendations from the Pediatric Endocrine Society for Evaluation and Management of Persistent Hypoglycemia in Neonates, Infants, and Children Paul S. Thornton, MB, BCh, Charles A. Stanley, MD, Diva D. De Leon, MD, MSCE, Deborah Harris, PhD, Morey W. Haymond, MD, Khalid Hussain, MD, MPH, Lynne L. Levitsky, MD, Mohammad H. Murad, MD, MPH, Paul J. Rozance, MD, Rebecca A. Simmons, MD, Mark A. Sperling, MBBS, David A. Weinstein, MD, MMSc, Neil H. White, MD, and Joseph I. Wolfsdorf, MB, BCh

Diagnosis and management of glycogen storage disease type I: a practice guideline of the American College of Medical Genetics and Genomics.

Disclaimer: This guideline is designed primarily as an educational resource for clinicians to help them provide quality medical services. Adherence to this guideline is completely voluntary and does not necessarily ensure a successful medical outcome. This guideline should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed toward obtaining the same results. In determining the propriety of any specific procedure or test, the clinician should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. Clinicians are encouraged to document the reasons for the use of a particular procedure or test, whether or not it is in conformance with this guideline. Clinicians also are advised to take notice of the date this guideline was adopted and to consider other medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures.Purpose:Glycogen storage disease type I (GSD I) is a rare disease of variable clinical severity that primarily affects the liver and kidney. It is caused by deficient activity of the glucose 6-phosphatase enzyme (GSD Ia) or a deficiency in the microsomal transport proteins for glucose 6-phosphate (GSD Ib), resulting in excessive accumulation of glycogen and fat in the liver, kidney, and intestinal mucosa. Patients with GSD I have a wide spectrum of clinical manifestations, including hepatomegaly, hypoglycemia, lactic acidemia, hyperlipidemia, hyperuricemia, and growth retardation. Individuals with GSD type Ia typically have symptoms related to hypoglycemia in infancy when the interval between feedings is extended to 3–4 hours. Other manifestations of the disease vary in age of onset, rate of disease progression, and severity. In addition, patients with type Ib have neutropenia, impaired neutrophil function, and inflammatory bowel disease. This guideline for the management of GSD I was developed as an educational resource for health-care providers to facilitate prompt, accurate diagnosis and appropriate management of patients.Methods:A national group of experts in various aspects of GSD I met to review the evidence base from the scientific literature and provided their expert opinions. Consensus was developed in each area of diagnosis, treatment, and management.Results:This management guideline specifically addresses evaluation and diagnosis across multiple organ systems (hepatic, kidney, gastrointestinal/nutrition, hematologic, cardiovascular, reproductive) involved in GSD I. Conditions to consider in the differential diagnosis stemming from presenting features and diagnostic algorithms are discussed. Aspects of diagnostic evaluation and nutritional and medical management, including care coordination, genetic counseling, hepatic and renal transplantation, and prenatal diagnosis, are also addressed.Conclusion:A guideline that facilitates accurate diagnosis and optimal management of patients with GSD I was developed. This guideline helps health-care providers recognize patients with all forms of GSD I, expedite diagnosis, and minimize adverse sequelae from delayed diagnosis and inappropriate management. It also helps to identify gaps in scientific knowledge that exist today and suggests future studies.Genet Med 16 11.

Liver transplantation in children with glycogen storage disease: Controversies and evaluation of the risk/benefit of this procedure

Abstract: GSD‐I, III, and IV are congenital disorders of glycogen metabolism that are commonly associated with severe liver disease. Liver transplantation has been proposed as a therapy for these disorders. While liver transplantation corrects the primary hepatic enzyme defect, the extrahepatic manifestations of GSD often complicate post‐transplantation management. Upon review of the English‐language literature, 42 children <19 yr of age were discovered to have undergone liver transplantation for complications associated with GSD (18 patients with GSD‐Ia, six with GSD‐Ib, one with GSD‐III, 17 with GSD‐IV). An additional two children followed at our institution have undergone liver transplantation for GSD complications (one with GSD‐Ia and one with GSD‐III) and are included in this review. The risks and benefits of liver transplantation should be considered prior to performing liver transplantation in these metabolic disorders, particularly in GSD‐Ia. As liver pathology is not the major source of morbidity in GSD‐Ib and GSD‐IIIa, liver transplantation should only be performed when there is high risk for HCC or evidence of substantial cirrhosis or liver dysfunction. Liver transplantation remains the best option for treatment of GSD‐IV.

2002 E. Mead Johnson Award for research in pediatrics lecture: The molecular biology of the anemia of chronic disease: A hypothesis

The anemia of chronic disease is a common disorder that afflicts patients with a wide variety of inflammatory conditions including arthritis, malignancies, infections, and inflammatory bowel disease. It results in significant morbidity and may be severe enough to require blood transfusions. The pathogenesis of anemia of chronic disease is not fully understood, but poor maintenance of red blood cell mass has been observed at three levels:1) iron is not efficiently recycled from reticuloendothelial macrophages to erythroid precursors, 2) erythroid precursors respond poorly to erythropoietin, and 3) red blood cell survival is decreased. Whether each of these changes is related to the same effector of the inflammatory process is unknown. We have had the opportunity to investigate severe anemia of chronic disease in an unusual group of patients with glycogen storage disease type 1a. We found that anemia was directly related to the presence of large hepatic adenomas that inappropriately produced a new peptide hormone, hepcidin. Hepcidin has recently been identified as part of the innate immune response and is a key regulator of cellular iron egress. Based on our findings in this patient group, we propose a central role for hepcidin in anemia of chronic disease, linking the inflammatory process with iron recycling and erythropoiesis. We present a hypothesis based on our findings.

GLYCOGEN STORAGE DISEASES: Phenotypic, Genetic, and Biochemical Characteristics, and Therapy

The glycogen storage diseases are caused by inherited deficiencies of enzymes that regulate the synthesis or degradation of glycogen. In the past decade, considerable progress has been made in identifying the precise genetic abnormalities that cause the specific impairments of enzyme function. Likewise, improved understanding of the pathophysiologic derangements resulting from individual enzyme defects has led to the development of effective nutritional therapies for each of these disorders. Meticulous adherence to dietary therapy prevents hypoglycemia, ameliorates the biochemical abnormalities, decreases the size of the liver, and results in normal or nearly normal physical growth and development. Nevertheless, serious long-term complications, including nephropathy that can cause renal failure and hepatic adenomata that can become malignant, are a major concern in GSD-I. In GSD-III, the risk for hypoglycemia diminishes with age, and the liver decreases in size during puberty. Cirrhosis develops in some adult patients, and progressive myopathy and cardiomyopathy occur in patients with absent GDE activity in muscle. It remains unclear whether these complications of glycogen storage disease can be prevented by dietary therapy. Glycogen storage diseases caused by lack of phosphorylase activity are milder disorders with a good prognosis. The liver decreases in size, and biochemical abnormalities disappear by puberty.