Blood Ketone Body Ratio Research Articles

Effects of partial deprivation of portal blood on arterial blood ketone body ratio in rabbits.

To examine the effects of portal blood deprivation on energy metabolism of the liver, we studied: (1) the ketone body ratio (acetoacetate/beta-hydroxybutyrate) in liver tissue, which is in equilibrium with the free NAD+/NADH ratio in liver mitochondria, in the ligated lobe (LL) and nonligated lobe (NLL), (2) the hepatic energy charge [EC = (ATP + 1/2 ADP)/(ATP + ADP + AMP)] in both LL and NLL, and (3) the arterial blood ketone body ratio (BKBR) after left portal vein branch ligation (PBL) in rabbits. As found in LL after PBL, portal blood deprivation decreased the tissue ketone body ratio. The EC in LL significantly decreased after PBL, but recovered 7 days after PBL since the LL became atrophic. The BKBR remained within the normal range, even when 60% of the total liver was deprived of portal blood.

Changes in blood ketone body ratio with reference to graft viability after liver transplantation in rats

Abstract. Arterial blood ketone body ratio (acetoacetate/3-hydroxybutyrate; KBR), which reflects hepatic mitochondria] redox potential, was measured during a 2-week period after orthotopic liver transplantation in three groups of rats: group 1, the isogenic combination of LEW (RT1l) graft to LEW recipient as control; group 2, the allogenic combination of ACI (RT1a) graft to LEW recipient without immunosuppressive treatment; and group 3, the allogenic combination of ACI to LEW with immunosuppressive treatment using cyclosporin (CyA). Isogenic recipients survived indefinitely. Allogenic recipients in group 2 had severe rejection with a mean survival of 10. 3 ± 0. 54 days, while 77. 8% of the allogenic recipients in group 3 survived more than 30 days. KBR of rats surviving more than 2 weeks in groups 1 and 3 gradually increased post-transplantation and was maintained at a high level. By contrast, though KBR in group 2 was restored at 3 days, it gradually fell and remained at a significantly low level (P< 0. 001). It is suggested that KBR provides an accurate indicator for evaluating metabolic viability of the critically deteriorating liver graft accompanied by severe rejection.

肝切除術後における血清胆汁酸と血中ケトン体比の相関関係に関する臨床的研究

肝切除術後における血清胆汁酸と血中ケトン体比の相関関係に関する臨床的研究

Analysis of Hemodynamics B. 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.

Is the deterioration of liver viability due to hepatic warm ischemia or reinflow of pooled-portal blood in intermittent portal triad cross-clamping?

The effects of hepatic warm ischemia and portal pooling on the viability of the liver were investigated with respect to hepatic energy metabolism by performing intermittent portal triad cross-clamping (Pringle's maneuver) on dogs with or without portosystemic shunt. The dogs were divided into two groups of five: Group 1, non-shunt group, underwent Pringle's maneuver performed for 30 min and declamping for 30 min, a process that was repeated five times; and Group 2, shunt group, underwent the same procedure as Group 1, except for portosystemic shunt using a heparinized hydrophilic catheter between the splenic and jugular veins. The shunt was opened during Pringle's maneuver and was closed immediately at declamping. In the non-shunt group, portal pooling increased and systemic blood pressure decreased when Pringle's maneuver was performed, but in the shunt group portal and systemic blood pressures remained within the normal range. In the non-shunt group, the initial velocity of arterial blood ketone body ratio (KBR) recovery after each declamping significantly (P less than 0.01) decreased from 0.122 +/- 0.016 (per min) after the first declamping to 0.028 +/- 0.017 (per min) after the fifth declamping. Hepatic energy charge [= (ATP + 1/2 ADP)/(ATP + ADP + AMP)] decreased from 0.840 +/- 0.003 before ischemia to 0.749 +/- 0.003 30 min after the fifth declamping (P less than 0.001). The concentrations of lactate and total amino acids in arterial blood increased. On the other hand, in the shunt group, the initial velocity of KBR recovery and hepatic energy charge showed little change even after the fifth declamping (0.081 +/- 0.016 per min and 0.851 +/- 0.009, respectively). The concentrations of lactate and total amino acids showed almost no increase. The impairment of hepatic energy metabolism by intermittent portal triad cross-clamping is mainly due to reinflow of pooled-portal blood to the previously ischemic liver, rather than hepatic warm ischemia. The KBR may be useful for determining the degree of impairment of hepatic energy metabolism.

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.

The effects of ulinastatin on the reticuloendothelial system (RES) of rabbits in endotoxin shock.

Carbon clearance, concentration of fibronectin (Fn) in the blood and arterial ketone body ratio (AKBR) have been measured in the rabbit in order to evaluate the RES phagocytic activity and the effect of ulinastatin on it in endotoxin (ET) shock. The following results were obtained: 1) carbon deposition by ET injection was found in organs (lung and kidney) which did not show it in the control group. The reasons for this might be considered that the RES was blocked because of phagocytizing ET and tissue debris, so that the carbon which could not be processed by the RES spilled over and became clogged; 2) the RES phagocytic activity were found to decline from an early stage after injection of a lethal dose of ET due to a decline in Fn productivity and an increase in Fn consumption; and, 3) ulinastatin suppressed the decrease of Fn and the carbon deposition in the kidney in ET shock. These results are suggestive of the usefulness of ulinastatin as an anti-shock agent, preserving the RES phagocytic activity through the inhibition of Fn consumption.

Arterial blood ketone body ratio as an indicator of the no-return point in hepatic inflow occlusion without venous shunt in dogs

The effects of hepatic inflow occlusion without venous shunt on the viability of the liver were investigated with respect to liver energy metabolism in dogs subjected to portal triad cross-clamping (Pringle's maneuver) for 10, 30 and 60 min. The concentrations of ketone bodies and the arterial blood ketone body ratio (KBR) were decreased markedly by hepatic inflow occlusion, but recovered upon recirculation. The initial velosity of KBR recovery was 0.150/min after 10-min clamping, 0.140/min after 30-min clamping and 0.032/min after 60-min clamping. KBR recovery was delayed when hepatic inflow occlusion exceeded 30 min, which indicates that hepatic inflow occlusion for 60 min causes severe inhibition of energy generation in liver mitochondria. These findings indicate that the safety period for hepatic inflow occlusion without venous shunt is between 30 and 60 min in dogs, and that mortality can be predicted by measuring the initial velosity of KBR recovery upon recirculation.

Graft transection and warm perfusion in situ in canine partial orthotopic liver transplantation.

Liver transplantation is now proven therapy for various forms of end-stage liver disease in children; however, the problem of donor liver shortage remains. To investigate the feasibility of graft procurement from living, genetically related adult donors without injury to either donor or recipient, partial orthotopic liver transplantation (PLT) using a graft transected and warm perfused in situ was evaluated in beagles; the viability of the graft was assessed in terms of energy metabolism, including blood ketone body ratio (KBR), as well as of recipient survival. PLT was performed in two groups with venovenous bypass. The left half of the donor liver was transected in situ, flush perfused with 2 l lactated Ringer's solution (4 degrees C in group A, 20 degrees C in group B), and immediately implanted into the recipient, who was totally hepatectomized, care having been taken to leave the inferior vena cava intact. Four of seven dogs survived for 5 days or longer (longest, 8 days) in group A and six of eight dogs (longest, 20 days) in group B. Causes of death were gastrointestinal bleeding, intussusception, or infection but not graft dysfunction. In both groups the KBR decreased significantly during the anhepatic period, recovered rapidly to the pre-anhepatic level after revascularization, and was maintained within a normal range thereafter. No significant differences in the time course of changes in KBR were seen between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in energy metabolism of allografts after liver transplantation.

To evaluate the function of energy metabolism in allografts after liver transplantation, changes in hepatic energy charge levels, oxidative and phosphorylative activities of mitochondria and arterial blood ketone body ratio (acetoacetate/3-hydroxybutyrate; KBR) were studied in piglets. Hepatic energy charge levels decreased to 0.831 +/- 0.010 at 3 days and 0.836 +/- 0.009 at 3 weeks after operation compared to the preoperative value of 0.868 +/- 0.006 (p less than 0.01), and returned to 0.856 +/- 0.007 at 6 weeks. Mitochondrial oxidative and phosphorylative activities were moderately enhanced to 19.14 +/- 2.07 (10(-10) mol ATP/mg of mitochondrial protein/s) at 3 days and 20.89 +/- 1.72 at 3 weeks compared to the preoperative value of 16.74 +/- 2.36, and returned to 16.65 +/- 1.54 at 6 weeks. There was no significant difference in the concentrations of mitochondrial respiratory components, except in cytochrome c + c1. KBR decreased immediately at the beginning of the anhepatic phase and rapidly recovered to the preoperative level within 60 min after revascularization of allografts. There was no change in KBR during the postoperative course except in cases with clinical deterioration. From these results, it is suggested that the mitochondrial capacity for ATP synthesis was enhanced to compensate for the decreased energy charge level and that a decreased KBR is a sign of a critically deranged metabolic function in allografts.

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.

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

The effects and safety limits of acute hemodilution on hepatic energy status were determined by comparison of arterial blood ketone body ratio (acetoacetate/3-hydroxybutyrate) 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 remnant liver than on the normal one.

Short-term changes in blood ketone body ratio in the phase immediately after liver transplantation.

Arterial blood ketone body ratio was measured after orthotopic liver transplantation in piglets. Ketone body ratio immediately decreased at the beginning of the anhepatic phase and was rapidly restored to the normal levels within 30 min after the revascularization of the allograft. Serum lactate and pyruvate levels increased in anhepatic phase and gradually decreased after revascularization. Changes in the lactate and pyruvate levels were always preceded by changes in ketone body ratio. In the case of transplantation after 12-hr-preservation of the allograft, ketone body ratio failed to maintain normal levels after transplantation, resulting in a high mortality. It is suggested that the elevation of decreased ketone body ratio is prerequisite for the normalization of the deranged metabolic state after liver transplantation, and that ketone body ratio provides an accurate means to assess the initial metabolic function of the allograft.

Acute responses of blood ketone body ratio following devascularization and revascularization of rabbit liver.

Acute changes associated with anhepatic and revascularized state were analyzed in relation to mitochondrial energy metabolism in rabbits. Fifteen minutes after the induction of anhepatic state, the ketone body ratio in the arterial blood decreased markedly from 0.833 to 0.229. The ketone body concentration also decreased to 24% of the normal value. The blood ketone body ratio and concentration remained low during the next 45 min. Pyruvate and lactate levels and the pyruvate/lactate ratio in the arterial blood changed very little during the 60-min anhepatic state. In a revascularization model following a 15-min anhepatic state, the ketone body concentration rose rapidly and then declined gradually, finally attaining a constant level at 30 min. The decreased blood ketone body ratio recovered to 0.55 at 30 min, and achieved steady state thereafter. Mitochondrial phosphorylative activity and hepatic energy charge showed almost normal levels 60 min after revascularization following the 15-min anhepatic state. These results indicate that the rapid metabolic alterations associated with the anhepatic and revascularized state can be accurately determined by measuring the arterial blood ketone body ratio, and they suggest that the ketone body ratio may serve as a convenient parameter for the evaluation of liver viability in pathological states such as operative ischemia or liver transplantation.

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%.

Effect of hepatic artery embolization on the adenylate energy charge level and the redox state of the cirrhotic liver.

Hepatic energy charge ((ATP + 1/2ADP)/(ATP + ADP + AMP)) and arterial blood ketone body ratio (acetoacetate/3-hydroxybutyrate) were measured after hepatic artery embolization in carbon-tetrachloride-induced cirrhotic rats. In normal livers, energy charge slightly decreased at 3 h and returned to normal levels at 6 h. By contrast, in cirrhotic livers, energy charge was drastically decreased at 3 h after embolization and was not completely recovered at 6 h. Blood ketone body ratio, reflecting hepatic mitochondrial redox (NAD+/NADH) state, also decreased at 3 h after embolization in both groups, and its recovery was not observed in cirrhotic group at 6 h.

Short-Term Changes in Blood Ketone Body Ratios in the Phase Immediately After Hepatic Artery Embolization: Their Clinical Significance

Changes in arterial and hepatic venous blood ketone bodies were investigated following transcatheter hepatic artery embolization (THAE) in patients with hepatocellular carcinoma. Acetoacetate/ beta-hydroxybutyrate ratio (ketone body ratio) in arterial blood was positively correlated with those of hepatic venous blood (r = 0.960, p less than 0.001), which reflects the mitochondrial redox potential in the embolized lobe. Nine cirrhotic patients were classified into three groups according to the changes in arterial blood ketone body ratio following THAE: Type A without decrease to below 0.7; Type B with a transient decrease to below 0.7, followed by its restoration within 5 hours; and Type C with decrease to below 0.7 without recovery within 5 hours. There were no serious complications in Type A and B patients. By contrast, severe sepsis and hepatic failure developed in Type C patients, possibly due to the extended embolization of both lobes. It is suggested that THAE can be successfully performed even in severely cirrhotic patients, as long as the embolized area is restricted to one lobe. In addition, changes in arterial blood ketone body ratios can give early information about the likely consequences of the THAE procedure just performed.

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.

Sequential changes in blood concentrations of fuels in relation to arterial blood ketone body ratio after 70% hepatectomy in rabbits.

The changes in arterial blood levels of glucose, free fatty acids, ketone bodies, and amino acids were investigated after 70% hepatectomy in rabbits in relation to the changes in adenylate energy charge of the remnant liver and ketone body ratio of arterial blood. Hepatic energy charge decreased to 0.767 +/- 0.008 within 24 h (p less than 0.001), and arterial blood ketone body ratio decreased to 0.415 +/- 0.041 within 12 h (p less than 0.001). Plasma free fatty acid concentrations increased to about twice the original values within 12 h (p less than 0.01), total amino acid concentrations also doubled within 24 h (p less than 0.01), and blood glucose levels decreased to below 100 mg/dl at 12 and 24 h (p less than 0.05). Afterward, at 96 h postoperatively (p.o.), blood ketone body ratio and energy charge levels were restored to near normal levels with the normalization of blood glucose, plasma free fatty acids, and plasma amino acids. These findings suggest that the decreased energy charge of the remnant liver concomitant with a fall in blood ketone body ratio may be the basis of the sequential changes in the blood concentration of fuels after massive hepatectomy.

Changes in acetoacetate/β-hydroxybutyrate ratio in arterial blood following hepatic artery embolization in man

Acetoacetate/β-hydroxybutyrate ratio in the hepatic venous blood was compared to the ratios in arterial blood and peripheral venous blood in hypoxic state following right hepatic artery embolization in 5 patients with liver cancer. Ketone body ratios in right hepatic venous blood were positively correlated with those in arterial blood (r=0.960, p<0.001), but not with those in peripheral venous blood. The free NAD +/HADH ratio of the liver mitochondria, which is reflected by the ketone body ratio in hepatic venous blood, can be evaluated by the ketone body ratio in the arterial blood.