Luis L. Mosovich

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

Hypophosphatasia: a developmental anomaly of alkaline phosphatase?

Extract: This report deals with quantitative and qualitative investigations of alkaline phosphatase in two unrelated infants with the severe infantile form of hypophosphatasia. Both affected infants had no detectable leukocyte alkaline phosphatase activities and both sets of parents and one sibling tended to have low but variable leukocyte enzyme activities. Normal duodenal juice alkaline phosphatase activity was present in the one patient in whom it was measured and a wide range of variation in enzymic activity was observed in the stools. There was no significant difference in the stool enzyme activity between both patients with hypophosphatasia (42.01 ± 9.77 U) and control infants (40.55 ± 6.29 U). However, the heterozygous parents had values significantly lower than the control adults (2.10 ± 0.47 as compared with 19.10 ± 4.44 U). Intestinal bacteria did not contribute significantly to the stool alkaline phosphatase activity. Enzyme activity was present in the bile of one of the patients and nearly absent in that of the other.Three “inducers” of alkaline phosphatase were given to both patients (phenobarbital, vitamin A, and corticosteroid). No clinical improvement or rise in serum alkaline phosphatase activity was observed during the trial of therapy with these agents. However, a significant increase in the activity of serum acid phosphatase was demonstrated during the course of vitamin A administration, suggesting an in vivo action of vitamin A on the lysosomes through decreasing the stability of the membrane and releasing acid phosphatase to the serum.Quantitative determination of tissue alkaline phosphatases from autopsy tissues was highly variable: no activity was found in bone, lungs, or spleen of either infant; there was a discrepancy in liver and kidney alkaline phosphatase values (zero in one patient and present in the other) and activity was present in the intestinal mucosa of both.Qualitative analysis of kidney, liver, and intestinal alkaline phosphatase revealed some differences between the patients and control subjects in heat inactivation and phenylalanine inhibition (Table 3). Starch gel electrophoresis of the liver preparation of one patient disclosed a single band which had greater mobility than that of six control subjects matched for age. Liver extracts from a premature and from full term newborns showed two bands. The single band of the patients liver enzyme corresponded to the newborns fast moving component. In addition, the intestinal enzyme prepared from the same patient had an extra band when compared with age-matched control subjects.Speculation: Among the many quantitative and qualitative alterations in alkaline phosphatases found in these two infants with the severe form of hypophosphatasia, the most striking finding was the presence in the liver of one of the cases of what appeared to be a form of the enzyme normally present only during very early postnatal life. The defective regulation of the various alkaline phosphatase isozymic forms during development may thus represent the basic defect in this disease.

Unusual biochemical and clinical features in a girl with ornithine transcarbamylase deficiency

A girl, ultimately diagnosed as having profound ornithine transcarbamylase (OTC) deficiency, presented as a neonate with feeding intolerance, irritability, and seizures without concurrent hyperammonemia. Developing normally until ten months of age, the girl subsequently experienced two episodes of hyperammonemia, which were associated with focal seizures and residual hemiparesis. She continued to have profound neurologic impairment and seizures and died at 26 months of age, despite appropriate dietary protein restriction, sodium benzoate, and arginine supplementation. Symptomatic OTC deficiency has not been previously reported unassociated with hyperammonemia. The recurrent cerebrovascular episodes are distinctly uncommon in patients with urea cycle enzymopathies.

EFFECTS OF PROTEIN LEVEL AND TYPE OF HEAT TREATMENT OF MILK FORMULAS ON GROWTH AND MATURATION OF INFANTS.

Four formulas designed to provide two levels of protein density and sterilized by two different methods (autoclaved and flash sterilized) were assigned to four groups of 27 infants for consumption from birth to 16 weeks of life. In the flash sterilized formulas, corn oil replaced butter fat. The weight gain and anthropometric performance were not significantly different among the various groups. The cholesterol levels in infants receiving formulas with butter fat (autoclaved) were higher than those receiving formulas with corn oil (flash sterilized). Blood urea nitrogen was higher in the infants consuming high-protein formulas. Infants receiving high-protein formulas consumed more calories. The caloric and protein efficiency ratios of low-protein formulas were significantly higher than those of the high-protein formulas, as were the ratios of the low-protein flash sterilized milks in comparison with the low-protein autoclaved ones. This latter difference could be evidence of protein injury resulting from autoclaving in the lower protein formulas.

PHARMACOKINETICS OF DICLOXACILLIN IN PATIENTS WITH CYSTIC FIBROSIS

The frequent episodes of peribronchial pneumonia seen in patients with cystic fibrosis require antibiotic administration often with anti-staphylococcal agents. Until now the data upon which to base dosage regimens have not been available. Serum dicloxacillin concentrations and urinary excretion rates were measured in 10 patients ranging in age from 9 to 22 years and in 5 normal adult subjects at various times after oral administration of a single dose (6.25 mg/kg) of antibiotic suspension in order to investigate absorption and disposition kinetics. The disease did not appear to cause impaired absorption of the antibiotic since the total urinary recovery of the drug in the patients usually exceeded that of normal subjects. However, the peak plasma levels and areas under the concentration versus time curves of dicloxacillin were much lower and more variable in the patients than in the normal subjects. Less antibiotic is therefore available for therapeutic effect. This was the result of unusually high renal clearances of dicloxacillin (3x normal). It was significant that the dicloxacillin:creatinine clearance ratios (1.55 versus 0.87, respectively) were larger in the patients than in normal subjects. Because of this rapid renal excretion, treatment of cystic fibrosis patients with dicloxacillin warrants use of increased doses. Measurements of the serum concentration of the antibiotic may be needed to assure adequacy of therapy.