Liver glucose-6-phosphatase and carbohydrate metabolism in childhood leukemia.

Abstract

Extract: Triplicate determinations of glucose-6-phosphatase activity in the 37,000 × g fraction of human liver homogenates were made. Table I summarizes the results from 100 consecutive autopsies. Enzyme activity for 78 nonleukemic children was 95 ± 66 (1 SD), and for 22 leukemic children was 17 ± 12 (1 SD) (p < 0.001). In the leukemic group there was no relation between the glucose-6-phosphatase activity with antileukemic drug therapy, the white blood cell count and the duration of the disease prior to death. The quantity of leukemic infiltrate in these livers varied, but there was no correlation between the extent of infiltration and enzyme activity. Several livers from leukemic children had no infiltrate and still had low glucose-6-phosphatase activities. One infant with liver glycogen disease had the expected reduction in glucose-6-phosphatase activity. A few children with other diseases (histiocytosis X, lupus erythematosis, aplastic anemia and retinoblastoma) had low enzyme activity in the liver. The time interval, 2-24 hours, between death and autopsy had no demonstrable effect on enzyme activity. Enzyme activity in nonleukemic liver diminished 5 %/day after storage up to 10 days and did not change significantly in leukemic livers. When 10 % liver homogenates, or the 37,000 × g fraction, was stored for 4 weeks at −20°C the percent of the original activity at 1, 2, 3 and 4 weeks was 70 %, 65 %, 53 % and 53 % respectively. A gradual, but significant, decline in human liver glucose-6-phosphatase activity occurs between birth and old age (fig. 2). Several potential inhibitors of enzyme activity were tested. The results are summarized in table II. Inhibition by p-chloromercuribenzoate and copper, and a lack of activation by magnesium are characteristic of this enzyme. Inhibition by sodium amytal was determined at pH 7.5 for both the control and the amytal-containing assays because of the poor solubility of amytal at pH 6.5. Table III summarizes the results of glucagon tolerance tests performed on leukemic children (7 in remission, 8 in relapse). It is apparent that the blood sugar rose higher at 15 and 30 minutes in the remission group than in the relapse group. The increase in both groups would probably be considered within the normal range, but the difference between them was significant (P < 0.05). Lactate concentration was determined on each serum specimen and did not vary in response to glucagon, but was significantly higher in relapse than in remission. The means for the relapse and remission groups were significantly different (P < 0.001) at each time interval. Serum lactate was determined on one leukemic child 4 hours before death and was 150 meq/L. Other enzyme activities which were determined on 8 leukemic and 8 nonleukemic livers after storage at −20°C an average of 10 (controls) and 15 (leukemics) weeks are summarized in table IV. Two fresh leukemic and two nonleukemic livers were also assayed for each activity. The average of these assays were (leukemic, nonleukemic): lactic dehydrogenase- 0.44, 0.40; glucose-6-phosphate dehydrogenase- 17.0, 8.5; adenosine triphosphatase 6.8, 14.0; inorganic pyrophosphatase 14, 33; fructose-1, 6-diphosphatase 6.0, 9.0. Four of the leukemic livers had no detectable lactic dehydrogenase activity (below 0.02), while the other four had activities comparable to that found in the nonleukemic livers. These data may be summarized as indicating that liver from children with leukemia had reduced glucose-6-phosphatase, inorganic pyrophosphatase, and sometimes had reduced lactic dehydrogenase activity. Glucose-6-phosphate dehydrogenase was increased 2-3 fold. Adenosine triphosphatase, fructose-1, 6-diphosphatase and glycogen were present in normal amounts. Speculation: Altered carbohydrate metabolism in children with terminal leukemia may have clinical manifestations (hypoglycemia and lactic acidosis) which are not commonly suspected. The possibility exists that these metabolic changes are part of the leukemic process rather than a result of it and relate to the basic pathology of neoplasma.