Toshio Nakatani

Changes in hepatic energy charge, blood ketone body ratio, and indocyanine green clearance in relation to DNA synthesis after hepatectomy

The changes in the energy charge (ATP + 0.5 ADP)/(ATP + ADP + AMP) levels of the remnant liver were studied in relation to changes in the incorporation rate of methyl-3H-thymidine into DNA, the blood ratio of acetoacetate/beta-hydroxybutyrate and indocyanine green (ICG) clearance in 70% hepatectomized rabbits. The energy charge levels of the remnant liver decreased rapidly to 0.767 from 0.856 of normal, despite a marked enhancement of mitochondrial phosphorylative activity, concomitant with the fall in blood ketone body ratio, before a maximal increase of DNA synthesis after hepatectomy. Blood ketone body ratio was correlated with hepatic energy charge (r = 0.696, p less than 0.01). After a maximal increase of DNA synthesis, hepatic energy charge levels and the blood ketone body ratios increased gradually to normal levels, concomitant with a rise in ICG clearance. Energy charge levels of the remnant liver can be evaluated by the blood ketone body ratio.

Changes in predominant energy substrate after hepatectomy

Abstract The changes in the energy substrate utilized by the remnant liver were studied in relation to the changes in the cellular energy status of 25 and 70% hepatectomized rabbits. In 25% hepatectomized rabbits, the energy charge ( ( ATP +0.5 ADP ) ( ATP + ADP + AMP ) ) level of the remnant liver remained unchanged, the energy substrate of which was predominantly glucose, rather than fatty acid. In contrast, in 70% hepatectomized rabbits, the energy production by the mitochondria was mainly dependent upon fatty acid oxidation at the early period after hepatectomy when the energy charge level decreased remarkably, and then upon glucose oxidation, concomitant with the restoration of the energy charge. It is suggested that the changes in the energy substrate utilized are closely related to those in the energy charge level and the mitochondrial phosphorylative activity of the remnant liver following hepatectomy.

The Influence of Hemodilution in Normal and Cirrhotic Rats in Relation to Hepatic Energy Metabolism

The effects of acute hemodilution on hepatic energy status were compared between carbon-tetrachloride-induced cirrhotic rats and normal rats, using arterial blood ketone body ratio and hepatic energy charge as indices. Arterial blood was withdrawn and replaced with rat plasma in hemodiluted rats and with whole blood in sham-diluted control rats. In normal rats, arterial blood ketone body ratio and energy charge level at 6 hours after hemodilution decreased when the hematocrit value was less than 15%. In contrast, the values decreased at an even higher hematocrit level in cirrhotic rats. It was suggested from these results that the hemodilution procedure exerts a more profound hypoxic effect at a milder hemodilution on a cirrhotic liver than on a normal liver.

Hyperglycemic hyperosmolar nonketotic dehydration in relation to blood ketone body ratio in partially hepatectomized rabbits

The ability of the liver to control blood glucose levels was studied in relation to the blood ketone body ratio, which reflects the hepatic mitochondrial redox state. In partially hepatectomized rabbits, postoperative continuous administration of a hyperosmolar glucose solution revealed the following findings: (1) The occurrence of glucose intolerance during postoperative hypertonic glucose administration was more dependent on the severity of the reduced hepatic mitochondrial redox state, as reflected by the blood ketone body ratio, than on the size of the liver remnant. (2) Insulin resistance developed when the redox state of the liver mitochondria was severely reduced. (3) It was very difficult to maintain the blood glucose level within normal range when the redox state was severely reduced. In patients, insufficient glucose administration can easily result in hypoglycemia, and excess administration can result in hyperglycemia, which might, in turn, result in hyperglycemic hyperosmolar nonketotic dehydration.

Influence of Hemodilution on Hepatic Energy Metabolism in Rat

The effects and safety limits of acute hemodilution on hepatic energy status were investigated in relation to arterial blood ketone body ratio and hepatic energy charge in a hemodilution rat model. As long as the hematocrit value was maintained above 20%, ketone body ratio and energy charge level at 6 h after hemodilution remained at the same levels as those of the sham-diluted groups. However, when hematocrit value was less than 15%, the ketone body ratio markedly decreased from the control value of 0.686 +/- 0.044 to 0.278 +/- 0.048 (p less than 0.001), and energy charge decreased from the control value of 0.856 +/- 0.012 to 0.0806 +/- 0.011 (p less than 0.01). From these results, it was suggested that hemodilution exerts no influence on the energy status of the liver as long as hematocrit is maintained above 20%.

Glucose intolerance and amino acid imbalance in relation to changes in blood ketone body ratio in hepatectomized rabbits.

Glucose metabolism and plasma amino acid pattern were investigated in relation to arterial blood ketone body ratio (acetoacetate/3-hydroxybutyrate), which reflects liver mitochondrial redox state, in rabbits subjected to graded hepatectomy (25, 70 and 93%) and 70% hepatectomy with common bile duct obstruction. After partial hepatectomy, blood ketone body ratio decreased according to the extent of resected mass. Common bile duct ligation induced a further decrease in blood ketone body ratio in 70% hepatectomized rabbits. During a 6-hour hypertonic glucose infusion (0.7 g glucose/kg/h) which started 24 h after the operation, the blood glucose level remained between 230 and 280 mg/dl in 25 and 70% hepatectomized groups, while it increased linearly in 93% and jaundiced 70% hepatectomized groups. The plasma concentrations of alanine and proline as well as other amino acids increased as the blood ketone body ratio decreased. It is suggested that Krebs cycle and gluconeogenesis activities are inhibited as blood ketone body ratio decreases markedly resulting in an impaired glucose tolerance and amino acid imbalance.

Analysis of hemodynamics and blood gas in relation to blood ketone body ratio in partially hepatectomized patients.

A total of 205 studies of hemodynamics and blood gas analyses were performed in relation to hepatic mitochondrial redox state in 23 partially hepatectomized patients. When the blood ketone body ratio (the ratio of acetoacetate to beta-hydroxybutyrate in arterial blood) decreased, that is when the hepatic mitochondrial redox state was reduced, a hyperdynamic state with increased cardiac index, decreased systemic and pulmonary vascular resistance together with decreased oxygen consumption was observed in spite of the increased oxygen availability. Inhibited oxidative metabolism in the Krebs cycle may have resulted in the decreased oxygen consumption and decreased vascular tone. This study supports the concept that the hepatic metabolic derangements due to reduced hepatic mitochondrial redox state may be a factor in the decreased oxygen consumption and hyperdynamic state.

The Influence of Hemodilution in Normal and Hepatectomized Rats in Relation to Hepatic Energy Metabolism

ABSTRACT: The effects and safety limits of acute hemodilution on hepatic energy status were determined by comparison of arterial blood ketone body ratio (acetoacetate/3-hy-droxybutyrate) and hepatic energy charge levels in 70% hepatectomized rats and nonhepatectomized rats. Arterial blood was withdrawn and replaced with rat plasma in hemodiluted rats and with whole blood in sham-diluted control rats. The arterial blood ketone body ratio at 6 hours after hemodilution in hepatectomized and sham-diluted rats (0.454 ± 0.037) was lower than that of nonhepatectomized and sham-diluted rats (0.686 ± 0.044). In hepatectomized groups, it decreased to 0.403 ± 0.043 when the hematocrit value was less than 20% and to 0.286 ± 0.031 when it was less than 15%. In hepatectomized rats, hepatic energy charge at 6 hours after hemodilution was 0.809 ± 0.021 in sham-diluted controls, but decreased to less than 0.8 when the hematocrit was less than 20%. On the other hand, in nonhepatectomized rats, the energy charge was greater than 0.8 even when the hematocrit was less than 15% These results suggest that hemodilution procedure exerts more profound hypoxic effect on the remant liver than on the normal one.

Changes in Blood Glucose Levels in Relation to Blood Ketone Body Ratio following Hypertonic Glucose Infusion in 70% Hepatectomized Rabbits

The effects of postoperative infusion of a hypertonic glucose solution on the blood glucose level, blood ketone body ratio (acetoacetate/beta-hydroxybutyrate), and plasma alanine and proline levels were studied in 70% hepatectomized rabbits (group A) and in rabbits 70% hepatectomized and, in addition, subjected to bile duct obstruction at 12 h after hepatectomy (group B). Glucose infusion was started at the end of hepatectomy and continued for 20 h. The blood glucose level in group A remained at approximately 300 mg/dl throughout the study; however, it reached 789 mg/dl in group B at 20 h. The blood ketone body ratio, which reflects hepatic mitochondrial redox potential, decreased from 0.90 +/- 0.09 in untreated rabbits to 0.38 +/- 0.05 in group A, and to 0.19 +/- 0.03 in group B at 20 h. As the blood ketone body ratio decreased, plasma proline and alanine levels increased rapidly (proline, r = -0.601, p less than 0.02; alanine, r = -0.640, p less than 0.001). In addition, the blood ketone body ratio was positively correlated with the hepatic energy charge level [(ATP + 0.5 ADP)/(ATP + ADP + AMP)] (r = 0.57, p less than 0.001). It is suggested that the entry of glucose and amino acids into the Krebs cycle is inhibited as the blood ketone body ratio decreases, and under such conditions the infused glucose tends to accumulate, resulting in severe hyperglycemia.

THE EFFECT OF FAT EMULSION ON HEPATIC MITOCHONDRIAL ENERGY STATUS AFTER DECOMPRESSION OF BILIARY TRACT OBSTRUCTION

黄疸軽減術後の脂肪乳剤投与の是非について, 実験動物を用いて検討した. 家兎に閉塞性黄疸を作成した後, これを解除し, 脂肪乳剤を負荷した. 耐糖能曲線がlinear patternを示す肝機能予備力の不十分な時期には, 脂肪乳剤負荷によってEnergy Chargeは低下し, 肝ミトコンドリアの酸化還元状態を反映する動脈血中ケトン体比は低下して, 電子伝達系が抑制されていることを示し, 脂肪乳剤投与は禁忌と考えられた. 一方, parabolic patternを示す肝機能予備力の回復した時期では, ミトコンドリアはやはり還元状態に傾いたが, Energy Chargeの上昇に照らして, これはβ酸化の亢進によるものと考えられ, 脂肪乳剤が良く利用されていることを示した.