Charles U. Lowe

STUDIES OF GLYCOGEN METABOLISM IN LIVER GLYCOGEN DISEASE (VON GIERKE'S DISEASE): SIX CASES WITH SIMILAR METABOLIC ABNORMALITIES AND RESPONSES TO GLUCAGON

Glycogen disease of the liver (von Gierkes disease) is a rare and incompletely understood disorder of childhood. It is characterized by defective breakdown of liver glycogen to glucose. In most cases, excessive liver glycogen deposition occurs, reaching levels as high as 14 to 17 per cent of the wet liver weight (1, 2). Major clinical manifestations include hepatomegaly; fasting hypoglycemia, acidosis and ketosis; delayed growth and development, and increased morbidity with even minor infections. The most severely affected children have usually died during infancy. Histologic studies of autopsy or biopsy specimens of liver reveal essentially normal architecture, but hepatic cells contain excessive amounts of glycogen and often, fat. The glycogen is usually normal in structure (3) and can be broken down to glucose by homogenates of normal animal or human liver (2, 4, 5). Spontaneous breakdown of glycogen during in vitro incubation of liver tissue from affected children is deficient (2, 4, 6). The currently accepted pathways of liver glycogen metabolism are summarized in Figure 1. It was formerly believed that glycogen was synthesized through the action of phosphorylase, the same enzyme that catalyzes its breakdown. However, it is now agreed that this reaction, which occurs readily in vitro, is not an important one in vivo (7), and that glycogen synthesis probably proceeds through the uridine-diphosphoglucose pathway described by Leloir and Cardini (8). Glycogen breakdown is mediated by phosphorylase

Studies in liver glycogen disease. Effects of glucagon and other agents on metabolic pattern and clinical status.

Abstract Clinical and biochemical studies in nine children with liver glycogen disease are reported. Major discrepancies were observed between in vitro determinations of hepatic enzyme activity and clinical findings in the subjects under study. In particular, there was no correlation between the levels of glucose-6-phosphatase measured in biopsy specimens of liver and the degree of fasting hypoglycemia. It is concluded that none of the enzymatic defects so far described account satisfactorily for the manifestations of liver glycogen disease. In most of the patients studied, hyperlacticemia was a prominent feature of the fasting state. Feeding or glucose infusion resulted in decrease of the blood lactate levels. Injection of glucagon appeared to induce hepatic glycogenolysis, but with lactate as the principal end product instead of glucose. Decrease in liver size was observed in these patients during glucagon infusion. Two patients behaved differently, however; lactate levels in their blood were normal during fasting, and administration of glucagon did not result in release of either glucose or lactate by the liver. In five of six patients so studied, the administration of glucagon after feedings resulted in sustained elevation of blood glucose levels, with an initial increase, then a sharp decrease in lactate levels in blood. After this, concentrations of lactate were maintained near normal levels for several hours. When long-acting glucagon was administered, the effects appeared to persist up to eight hours. Explanations are suggested for the fasting hyperlacticemia, acidosis and ketosis of liver glycogen disease and for the characteristic hyperlipemia and fat accumulation in the liver. Postprandial injections of glucagon may be useful in the management of some children with liver glycogen disease.

LIVER GLYCOGEN DISEASE IN TWO GENERATIONS OF A FAMILY. CLINICAL STUDIES AND TISSUE ANALYSES DURING OVERT DISEASE AND AFTER APPARENT RECOVERY.

Abstract The diagnosis of liver glycogen disease has been established in a twenty-three year old man and in his two year old son, thus providing direct evidence in support of the hypothesis that this disease is genetically determined. Clinical, biochemical and histologic findings were identical in both patients. Both suffered from a type of glycogen disease characterized by hepatomegaly, abnormally high liver glycogen concentration and moderate growth retardation during childhood, but without clinically significant hypoglycemia, abnormalities of lipid metabolism or impairment of the hyperglycemic response to glucagon. As in other forms of liver glycogen disease, certain persistent abnormalities could be demonstrated in the adult patient, despite apparently complete clinical recovery from the disease.