Robert A. Cannon

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

Selenium Responsive Myositis during Prolonged Home Total Parenteral Nutrition in Cystic Fibrosis

The need for routine supplementation of total parenteral nutrition solutions with selenium (Se) has not been clearly defined. Although clinical selenium deficiency in patients on prolonged total parenteral nutrition has been reported, it is rarely observed in the United States. We report a 19-year-old woman with cystic fibrosis who developed muscle pain and weakness after 3 months on total parenteral nutrition which was not supplemented with Se. Coincident with her onset of symptoms, markedly elevated serum creatine kinase values were observed compared to baseline levels. Subsequent evaluations revealed undetectable (less than 0.02 microgram/ml) serum and urine Se levels in this patient. In addition, electromyographic evidence of myositis and nonspecific membrane irritability was documented. Therapy with oral Se rapidly reversed her symptoms and normalized with serum creatine kinase values over a 10-day period. Prolonged treatment with Se was required to achieve normal values of Se in the serum. Patients with severe pancreatic insufficiency, such as cystic fibrosis, may be at risk for clinical Se deficiency if on prolonged total parenteral nutrition without supplementation. Elevated creatine kinase levels should alert physicians to the possibility of Se deficiency in such patients.

Biochemical and ultrasonic abnormalities of the pancreas in anorexia nervosa

Seven of 10 patients with anorexia nervosa had ultrasonic and/or biochemical abnormalities of the pancreas. Seven patients had elevated amylase creatinine clearance ratios (>4%), three patients had elevated serum amylase values (>90 units/liter), and three patients had reduced echogenicity of the pancreas. There was no consistent association between presenting abdominal symptoms and abnormal ultrasonic and biochemical studies of the pancreas. After nutritional repletion, all studies reverted to normal. An eleventh patient, who was initially diagnosed as having anorexia nervosa but later found to have an astrocytoma of the medulla, had reduced echogenicity of the pancreas, suggesting malnutrition as the cause of these abnormal pancreatic studies. Pancreatic abnormalities due to protein-calorie malnutrition may be common in anorexia nervosa and must be differentiated from primary pancreatitis.

Experience with home parenteral nutrition

Twenty-nine patients underwent courses of home parenteral nutrition therapy ranging from 1.5 to 52 months (mean 14.5 months). The primary diagnoses responsible for the requirement of home parenteral nutrition were radiation enteritis in seven patients, short bowel syndrome secondary to resection in seven, Crohns disease in two, malabsorption states in six, and other reasons in seven. Seventeen patients (57 percent) had at least one complication. Nine patients had intravenous catheter complications and nine had metabolic complications. Nine patients have died, 11 have been successfully weaned from home parenteral nutrition, and 9 continue to receive home parenteral nutrition. Home parenteral nutrition is useful in a variety of catastrophic clinical situations, including preparation for subsequent operative therapy, temporary malabsorption, and permanent disability of the gastrointestinal tract. Complications are frequent and may be life-threatening.

Hepatobiliary scintigraphy with technetium-99m disofenin in the evaluation of neonatal cholestasis.

To assess the reliability of technetium-99m disofenin scanning in evaluating neonatal cholestasis, 33 neonates (less than 3 months of age) with direct hyperbilirubinemia were evaluated prospectively by cholescintigraphy. Results of this test were compared to those of standard serum tests of liver function, ultrasonography, and liver biopsy. The diagnosis of biliary atresia was suggested by a serum gamma-glutamyl transpeptidase (gamma-GTP) greater than 300 units/L, absence of the gallbladder on ultrasonography, and a lack of detectable radioisotope in the gastrointestinal and/or extrahepatic biliary tract on cholescintigraphy. Each of these tests lacked sensitivity and/or specificity when compared to liver biopsy. Of the nine neonates with biliary atresia, three had gallbladders identified by ultrasonography and two had gamma-GTP less than 300 units/L. Of the 24 neonates without biliary atresia, eight had cholescintigraphy without detectable radioisotope excretion, four had ultrasonography that failed to visualize the gallbladder, and nine had gamma-GTP greater than 300 units/L. Cholescintigraphy excluded the diagnosis of biliary atresia when gut and/or extrahepatic biliary excretion of isotope was seen. However, cholescintigraphy required more time, 6-8 days, and was less specific than ultrasonography and liver biopsy. We recommend that cholescintigraphy should not be routinely used in evaluating neonatal cholestasis, especially if it delays surgical intervention.

Gastrointestinal hemorrhage due to Mallory-Weiss syndrome in an infant.

A Mallory-Weiss tear of the gastroesophageal mucosa is reported as an unusual cause of upper gastrointestinal bleeding in a 3-week-old infant. The lesion, documented by endoscopy, appeared to follow hiccups. The bleeding responded to conservative medical management and resolved without surgical intervention.

Biliary obstruction in infants with cystic fibrosis requiring Kasai portoenterostomy

Cystic fibrosis is associated with an inspissated bile syndrome producing cholestasis secondary to plugging of macroscopically normal bile ducts. In extreme neonatal forms, with early profound intrahepatic cholestasis, the process can be associated with a marked decrease in ductal diameter, varying from hypoplasia to atresia. From 1990 to 1995 three infants were identified with cystic fibrosis, persistent jaundice, and complete absence of biliary excretion despite expectant and conservative treatment including choleretics and surgical biliary irrigation. Abdominal ultrasounds showed contracted gallbladders and no evidence of dilated ducts. Liver biopsy results in two infants showed portal fibrosis, paucity of bile ducts, and minimal inflammation. The third infant had moderate inflammation, bile duct replication, and plugging. Two infants had undergone intestinal resection followed by hyperalimenation for complications of meconium ileus in the newborn period. Surgical exploration was undertaken at 7 to 12 weeks of age. Gross findings were typical of biliary atresia with microgallbladders and nonpatency of the cystic duct. Cholangiograms failed to document ductal patency in two patients who were then treated with a Kasai portoenterostomy. The third infant had patent hypoplastic ducts and underwent only biliary irrigation. Although bile flow was transiently achieved, jaundice recurred, and at reexploration at 16 weeks of age a Kasai poroenterostomy was performed. Histological review of the biliary specimens showed microscopically patent ducts in two patients and proximal patency and distal atresia in the third. All the ducts had mural fibrosis with cystic changes. Bile drainage was achieved in each instance, although in one patient with hypoplastic ducts scant output of highly concentrated bile proved insufficient to arrest progressive liver failure. The subsequent two patients responded with resolution of hyperbilirubinemia and normalization of liver function. They remain free of biliary complications at 30 and 40 months postoperatively. This manifestation of cystic fibrosis in infants is suggested by prolonged jaundice unresponsive to choleretics, nondilated bile ducts and gallbladder on ultrasound, absent biliary excretion on nuclear scan, and characteristic liver biopsy. Exploration is warranted, and discovery of atrophic bile ducts may be best managed with reconstruction.

Gastroesophageal scintigraphy with and without compression.

This study compares the results of radionuclide gastroesophagography performed by the compression and computer-assisted noncompression techniques. The overall accuracy of the compression and noncompression methods was 71% and 84%, respectively. The use of computer processing significantly enhances the ability to detect minor degrees of reflux and may explain the better results obtained with the noncompression method. Other advantages of the noncompression technique include its technical ease and uniformity and the acquisition of more physiologic data for comparison with results of the acid reflux test.

BARRETT'S EPITHELIUM RESULTING FROM CHRONIC GASTROESOPHAGEAL REFLUX |[lpar]|GER|[rpar]| IN CHILDREN

Histologic changes seen on esophageal biopsies in children with GER may include normal squamous epithelium, changes in rete peg height & inflammatory infiltrates of PMNs or eosinophils. While severe GER in adults may be accompanied by replacement of normal esophageal epithelium with columnar epithelium (Barretts epithelium), this complication is not appreciated in children.4 children (ages 2-10 yrs) with severe GER complicating mental deficiency syndromes or multiple congenital abnormalities (VATER syndrome) were found to have Barretts esophagus. Severe GER was documented in each : UGI (+4/4), Tc99m milk scan (+4/4), 24 hr. esophageal pH monitoring (+4/4). The endoscopic appearance of the mucosa was consistent with moderate esophagitis in 3/4, mild esophagitis in 1. Biopsies were obtained at least 3 cm proximal to the GE junction or at an area of demarcation between normal and abnormal mucosa. All patients had evidence of gastric columnar epithelium upon histological examination of the tissue; 3/4 showed fundal mucosa with chief cells, 1 showed junctional type mucosa. In addition, all patients had infiltrates of chronic inflammatory cells in the lamina propria. 3/4 patients underwent elective fundoplication.Conclusion: Barretts epithelium may be seen as a complication of GER in children. Because the natural history of Barretts following correction of GER is unknown in children, careful survalence is indicated due to the premalignant potential of these changes.

DISORDERED ESOPHAGEAL, COLONIC, AND RECTAL MOTILITY IN INFANT BOTULISM

Impairment of both autonimic & voluntary neuromuscular transmission due to C. botulinum toxin in infants is recognized. Abnormalities of gastrointestinal motility in cases of infant botulism have been identified, but not fully defined. Four infants (ages: 5-9 mos.) with documented botulism (Type A:2, Type B:2) were evaluated for disordered esophageal, rectal, & colonic motility. Esophageal manometrics documented normal lower esophageal sphincter pressures ([xmacr ]:24 mm Hg; N:20-35) and relaxation. Distal (smooth muscle) peristalsis was normal, but proximal (striated muscle) peristalsis was absent in all patients. In addition, upper esophageal sphincter achalasia was documented in each. The resolution of the proximal esophageal dismotility was associated with overall clinical improvement and return of skeletal muscle strength.Rectal-colonic manometrics revealed low anal pressure profiles ([xmacr ]:45 mm Hg; N:80-120) with normal internal sphincter relaxation; 2/4 patients exhibited delayed return of resting pressures. Colonic EMG slow waves were observed with a frequency of 3-4 cycles/minute. Colonic spike bursts were observed, but not correlated with intraluminal pressure changes during the acute stage.Significant dismotility of the proximal esophagus is present during the acute phase of infant botulism and contributes to the dysphagia observed clinically. Disordered intraluminal colonic motility may account for the frequent observation of constipation, as rectal sphincter reflexes are preserved.