Journal of Gastroenterology and Hepatology (1990) 5 , 296-309
REVIEW ARTICLE Hepatic function and liver resection KAZUE OZAWA Second Department of Surgery, Kyoto University Medical School, Kyoto, Japan
INTRODUCTION Absolute cure of liver cancer can be achieved only by the complete resection of the tumour, removing the surrounding liver tissue in as large a volume as possible along with the tumour. Underlying cirrhosis, however, often makes the resection extremely vulnerable to posthepatectomy liver failure, leading to multiple organ failure. Accordingly, it is important to have a prognostic tool to assess the risk of operation in cirrhotics prior to hepatectomy. Investigators have documented well the high risk of morbidity and mortality associated with hepatectomy and portasystemic shunt procedures in cirrhotics. The most widely accepted method to estimate more accurately surgical risk prior to portasystemic shunt operation is Child's classification, a multifactorial index, which has been modified in various However, it must be said that the prediction of post-hepatectomy liver failure in the individual cirrhotic patient cannot be made with any accuracy with any of these methods of evaluation. The measurement of uptake of organic anions such bromosulfophthalein (BSP), rose bengal, and indocyanine green (ICG) as a load test has been one of the more sensitive indicators of liver disease, and ICG retention rate or KrCGare generally considered as routine procedures. However, JCG removal rate at the usual dose employed has not enabled the quantification of the degree of hepatic functional reserve, although it may demonstrate hepatic circulation rate.
Paumgartner et al. and Moody et al. have postulated that maximal removal rate of ICG might provide a measure of hepatic functional reserve.'"' Two other groups in Japan have tried to reduce the operative mortality by combined volumetric and functional estimation of parenchyma remaining after resection. Mizumoto et al. have reported that, prior to hepatectomy, the functional reserve of the remnant liver can be estimated from two factors: (i) an effective liver volume rate, calculated from the rate of uptake of radio-isotope as measured by on-line computer system; and (ii) ICG R,,,.9 On ICG R,,, of the remnant liver, all patients tolerated well any kind of hepatectomy when it was more than 0.4 mg/kg per min, but all cases developed severe hepatic insufficiency when it was below 0.4 mg/kg per min. Since ICG R,,, is less significant than the ICG retention rate, Okamoto et al. have reported the pre-operative estimation of the safety limits of hepatic resection using two factors: (i) the remnant hepatic volume; and (ii) the ICG retention at 15 min (ICG Rls). However, they found that there is a limit to the predictability of posthepatectomy liver failure by this method. In order to predict more accurately early survival following hepatectomy, they developed a more useful prognostic index using the following multiple regression equation:
+
+
+
Prediction score = - 110 0.942a 1.366 1 . 1 7 ~ + 5.94d where a =resection rate (YO),6 = ICG retention
Correspondence: Prof. K. Ozawa MD, Department of Surgery 11, Kyoto University Hospital, Kawahara-cho Shogoin, Sakyo-ku, Kyoto, 606 Japan. Accepted for publication 10 April 1989.
297
Hepatic function and liver resection rate (X), c=patient's age (years) and d = ICG maximal removal 'rate (mg/kg per min)." When the prediction score was 6 5 0 points, a major hepatectomy could be done successfully; when it was 2 5 0 points, a subsegment or a wide wedge resection was recommended. Recently, Bismuth et al. have reported that most cases of posthepatectomy liver failure were in fact precipitated by an additional complication such as sepsis, haemorrhage, portal thrombosis, etc.I2 Therefore, the ultimate outcome in an individual patient is not easily determined prior to the procedure. We have also pointed out that the most important factors initiating posthepatectomy liver failure are excessive surgical stress and poor postoperative management, rather than excessive resection of functional parenchyma, as described later. Generally, the pre-operative estimation of hepatic functional reserve by an ICG clearance and a multiple regression equation has been defined retrospectively with postoperative results based on the experience of each surgeon, such as the morbidity or mortality of each patient. In the actual postoperative course of hepatectomized patients, liver insufficiency sometimes occurs unexpectedly even after good pre-operative evaluation of hepatic functional reserve. The pre-operative estimation of hepatic functional reserve by an analysis of the operative results based on the experience of each surgeon can be done only with great uncertainty. In addition, with regard to this point, other crucial factors such as the influences of surgical stress and postoperative management are not considered. If surgeons are too concerned with operative safety and make their evaluation on the basis of these preoperative evaluations alone, the decrease of hepatic functional reserve is apt to be grossly overestimated, with the result that not only will the hepatic resection for liver cancer be incomplete, but also that the cirrhotic patient who is actually resectable will be abandoned as an unresectable case. An infinite capacity for regeneration complicates quantitative assessment of hepatic functional reserve following hepatectomy. Therefore, in order to increase the resectability and radicality of hepatic malignancies, greater efforts should be placed on the total programme of pre-, intra- and postoperative assessment of the metabolic capacity of the remnant liver following hepatectomy.
CHANGES IN THE ENERGETIC METABOLISM FOLLOWING HEPATECTOMY The vital function of the remnant liver essential to survival following hepatectomy depends on the continuous supply of energy produced in mit0ch0ndria.l~ In considering energy metabolism, it is essential to clarify the fundamental nature of the derangement of the energy balance in the remnant liver after hepatectomy. A very convenient expression of this balance is the concept of energy charge (ATP+ 1/2 ADP)/(ATP+ADP+AMP), which is designated by Atkinson as the regulator of the metabolic processes.14Energy charge is a major factor in the regulation of pathways that produce and utilize high-energy phosphate compounds. The energy charge value reflects the cellular energy balance between the energygenerating and energy-utilizing sequences, and is maintained at 0.85-0.90 in normal cells. The regulation of energy generation assures a continuing supply of ATP commensurate with current requirements. In the cells, the mitochondria regenerate ATP at sufficiently rapid rates to maintain a normal energy charge, despite the many enzymatic reactions that utilize ATP. If the energy charge decreases, the ATP-generating sequences are accelerated and the ATP-requiring sequences are slowed down. The energy charge strongly resists any deviation from 0.85, and cellular viability declines with a fall in energy charge. Figure 1 shows the time course of changes in ICG clearance, the ratio of acetoacetate to 3-hydroxybutyrate in arterial blood (KBR), mortality rate, and mitochondria1 phosphorylative activity, energy charge and DNA synthesis of the remnant liver after 70% hepatectomy of rabbits.ls-" The ratio of acetoacetate to 3-hydroxybutyrate (KBR) reflects the ratio of free oxidized: reduced nicotinamide adenine nucleotide in liver mitochondria.18The KBR decreased rapidly to 0.44from 0.93 at 12 h after hepatectomy. Mitochondria1phosphorylative activity increased to 1 7 0 4 ~ of~control, and the energy charge level decreased to 0.767 at 24 h after hepatectomy, after which these values returned to pre-operative levels within 1 week. The mortality rate of hepatectomized rzbbits was highest at 24 h after hepatectomy, when the energy charge levels of
K.Ozawa
298
0
1
2
3 4 5 6 Days after hepatectomy
7 1 4 4 2
Figure 1 Time courses of changes in blood ketone body ratio, ICG clearance, mortality rate, and mitochondrial ATP synthesis, energy charge and DNA synthesis of the remnant liver after 70% hepatectomy of rabbits. Each point represents the mean and standard error of values for six or more animals.
the remnant liver had decreased markedly. During this period of maximum metabolic load, the delicate energy balance in the renmant liver was barely maintained by a compensatory enhancement of mitochondrial phosphorylative activity. Once this stage was passed, however, DNA synthesis was increased concomitantly with the restoration of the energy charge to about 0.80 at 48 h after hepatectomy at which the percentage K of ICG began to increase significantly. Consequently, successful hepatectomy may be said to be a matter of successfully passing through this critical stage. Decreased energy charge may be regarded as one of the most fundamental factors contributing to hepatic failure after major hepatic resection.
The KBR, which is positively correlated with hepatic energy charge, may be regarded as reliable indicator by which to assess the severity of decreased energy charge following hepatectomy. An enhancement in mitochondrial phosphorylative activity of the remnant liver following hepatectomy is the adaptive response of the mitochondria to restore the energy charge in response to a high demand for energy. If the mitochondria cannot produce sufficient ATP to normalize the energy charge, the hepatectomized patient may die of an acute energy crisis. Thus, an analysis of these biochemical events occurring in the mitochondria provides a valuable means of evaluating the potency of the compensatory and regenerative capacity of the liver.
299
Hepatic function and liver resection
EVALUATION OF H E P A T I C FUNCTIONAL R E S E R V E P R I O R T O HEPATECTOMY
loo-. 80
Cytochrome a (+ a3) assay
In cirrhotic liver, the mitochondrial phosphorylative activity cannot be enhanced sufficientlyto overcome the metabolic load imposed on the remnant liver following h e p a t e ~ t o m y . ' ~In - ~the ~ cirrhotic liver, the decrease in mitochondrial phosphorylative activity per unit of respiratory assemblies was negatively correlated with the increase of mitochondrial respiratory enzymes, especially cytochrome a ( + a3),24*28 and positively with the decrease of hepatic energy charge.lg Thus, an increase in cytochrome a( + a3) concentration is one of the most important indices for predicting the decreased functional reserve of cirrhotic patients. Clinically, cirrhotic patients with normal or moderately increased concentrations of cytochrome a( + a3) tolerated major operations well, whereas those with markedly increased cytochrome a( + a3) concentrations had high rates of postoperative morbidity and mo~a~~ty~zz.z~~z~.a~.~~
In our department, a careful assay of cytochrome a( +a3) using about 1g of biopsy material is routinely performed prior to contemplated major hepatic resecti~n.'~As long as the concentrations of cytochrome a( + a3) of motochondria from the remaining liver range from 0.7-1.3 x mol/mg protein, major hepatic resection can be performed without complication or death (Fig. 2). Patients with markedly increased cytochrome a( +a3) concentrations (> 1.5 x mol/mg protein) are less than ideal operative candidates, and the percentage of liver resection should be restricted to less than 40%. Other recent studies from our department have shown that the liver with concentrations of mol/mg procytochrome a( +a3) > 1.5 x tein is associated with severe piecemeal necrosis.33 When the concentration of cytochrome a( + a3) is cO.5 x mol/mg protein, even a supposedly 'minor' operation to remove 20% of the liver should definitely be avoided. Furthermore, based on the observation that the cytochrome c oxidase activity per unit wet weight of liver correlates positively with the amount of cytochrome a( + a3) in mitochondria, we have developed a technically simple and rapid method for the evaluation of
-
-ae& 60-
-
> .C
40a:
0
0.4 0.8 1.2 1.6
2.0
Cytochrome a (+as) concentration (x 10-10 mol/mg protein) Figure 2 Percent of remnant liver and cytochrome a(+a3) concentrations in hepatectomized patients with an uneventful course (0), with postoperative complications ( O ) ,and who died after surgery ( 0 ) .
mitochondrial function by measuring V , or K, of cytochrome c oxidase activity using 10-20 mg needle biopsy material^.^^ Glucose tolerance
In oral glucose tolerance test (GTT), an increase in the hepatic energy charge correlated positively with an increase in the blood glucose, plasma immunoreactive insulin (IRI) levels and the redox potential (NAD+/NADH) of the r n i t o c h ~ n d r i a . ~The ~ - ~possible ~ relationship between phosphorylative activity per unit of cytochrome a( +a3) and glucose tolerance pattern is illustrated in Fig. 3. When the hepatic energy charge is within normal limits, the G T T patterns are parabolic. It is only with the marked decrease of hepatic energy charge that linear G T T patterns develop. These patterns are also reflected in the changes in the phosphorylative activity of the liver mitochondria. In instances in which the phosphorylative activity of liver mitochondria is within normal limits, the parabolic G T T pattern occurs, but when it increases or decreases markedly, the linear G T T patterns develops. Such considerations make it essential to learn more about the changes in glucose tolerance
K. Ozawa
300
/
Decreased
J
NOr ma I
Mitochondr ial phosphorylative activity
I
Normal
(hours)
1
(hours)
Decreased
(hours)
Figure 3 Glucose tolerance curve and hepatic energy charge after an oral glucose load. in hepatectomized patients. G T T could provide at least some prognostic information concerning operative risk, late survival, and the likelihood of early postoperative liver failure in hepatectomized patients. The glucose tolerance of liver cancer patients was principally classified into two groups: the parabolic pattern which tended to exhibit a return of blood glucose level toward normal limits within 120 min (parabolic G T T pattern), and the gradually increasing pattern having no return toward normal limits within 120 min (linear G T T pattern). In addition, it has been found that, even when the G T T pattern is parabolic, hepatic failure easily occurs following hepatectomy when insulin response to a glucose load is suppressed. Measurements of glucose tolerance and plasma insulin level thus enable preoperative separation of patients into four groups with markedly different postoperative prognoses: (i) parabolic G T T pattern with normal or higher insulin secretion; (ii) parabolic G T T pattern with
suppressed insulin secretion (iii) linear G T T pattern with norm1 or higher insulin secretion; and (iv) linear G T T pattern with suppression of insulin ~ e c r e t i o nTherefore, .~~ for successful massive hepatectomy, in addition to the measurement of cytochrome a( + a3) in the remnant liver, it is very important that the patient possesses both a normal or parabolic G T T pattern and a normal insulin secretion from the pancreas after an oral glucose load. Redox tolerance test Glucose tolerance pattern has been found to be closely related to the decrease in hepatic energy charge and the decreasc of redox potential (NAD+/NADH) of liver mitochondria. In this regard, the measurement of the changes in arterial blood ketone body ratio after an oral glucose load, the redox tolerance test (RTT), is useful for evaluating hepatic functional reserve in cirrhotic patients.
301
Hepatic function and liver resection In a study comparing the cumulative enhancement of blood glucose and blood ketone body ratio after an oral glucose load between normal and cirrhotic patients, we found that the AKBR:Aglucose ratio serves as a rapid and accurate indicator for the pre-operative evaluation of the hepatic functional reserve, especially in cirrhotic patients. In 79 hepatectomized patients, the preoperative values of AKBRIA glucose were estimated from the changes in the postoperative blood ketone body ratios (Fig. 4).The values of AKBR/ Aglucose were classified into two groups - group I:> 0.5 ( x and group 11:
REVIEW ARTICLE Hepatic function and liver resection KAZUE OZAWA Second Department of Surgery, Kyoto University Medical School, Kyoto, Japan
INTRODUCTION Absolute cure of liver cancer can be achieved only by the complete resection of the tumour, removing the surrounding liver tissue in as large a volume as possible along with the tumour. Underlying cirrhosis, however, often makes the resection extremely vulnerable to posthepatectomy liver failure, leading to multiple organ failure. Accordingly, it is important to have a prognostic tool to assess the risk of operation in cirrhotics prior to hepatectomy. Investigators have documented well the high risk of morbidity and mortality associated with hepatectomy and portasystemic shunt procedures in cirrhotics. The most widely accepted method to estimate more accurately surgical risk prior to portasystemic shunt operation is Child's classification, a multifactorial index, which has been modified in various However, it must be said that the prediction of post-hepatectomy liver failure in the individual cirrhotic patient cannot be made with any accuracy with any of these methods of evaluation. The measurement of uptake of organic anions such bromosulfophthalein (BSP), rose bengal, and indocyanine green (ICG) as a load test has been one of the more sensitive indicators of liver disease, and ICG retention rate or KrCGare generally considered as routine procedures. However, JCG removal rate at the usual dose employed has not enabled the quantification of the degree of hepatic functional reserve, although it may demonstrate hepatic circulation rate.
Paumgartner et al. and Moody et al. have postulated that maximal removal rate of ICG might provide a measure of hepatic functional reserve.'"' Two other groups in Japan have tried to reduce the operative mortality by combined volumetric and functional estimation of parenchyma remaining after resection. Mizumoto et al. have reported that, prior to hepatectomy, the functional reserve of the remnant liver can be estimated from two factors: (i) an effective liver volume rate, calculated from the rate of uptake of radio-isotope as measured by on-line computer system; and (ii) ICG R,,,.9 On ICG R,,, of the remnant liver, all patients tolerated well any kind of hepatectomy when it was more than 0.4 mg/kg per min, but all cases developed severe hepatic insufficiency when it was below 0.4 mg/kg per min. Since ICG R,,, is less significant than the ICG retention rate, Okamoto et al. have reported the pre-operative estimation of the safety limits of hepatic resection using two factors: (i) the remnant hepatic volume; and (ii) the ICG retention at 15 min (ICG Rls). However, they found that there is a limit to the predictability of posthepatectomy liver failure by this method. In order to predict more accurately early survival following hepatectomy, they developed a more useful prognostic index using the following multiple regression equation:
+
+
+
Prediction score = - 110 0.942a 1.366 1 . 1 7 ~ + 5.94d where a =resection rate (YO),6 = ICG retention
Correspondence: Prof. K. Ozawa MD, Department of Surgery 11, Kyoto University Hospital, Kawahara-cho Shogoin, Sakyo-ku, Kyoto, 606 Japan. Accepted for publication 10 April 1989.
297
Hepatic function and liver resection rate (X), c=patient's age (years) and d = ICG maximal removal 'rate (mg/kg per min)." When the prediction score was 6 5 0 points, a major hepatectomy could be done successfully; when it was 2 5 0 points, a subsegment or a wide wedge resection was recommended. Recently, Bismuth et al. have reported that most cases of posthepatectomy liver failure were in fact precipitated by an additional complication such as sepsis, haemorrhage, portal thrombosis, etc.I2 Therefore, the ultimate outcome in an individual patient is not easily determined prior to the procedure. We have also pointed out that the most important factors initiating posthepatectomy liver failure are excessive surgical stress and poor postoperative management, rather than excessive resection of functional parenchyma, as described later. Generally, the pre-operative estimation of hepatic functional reserve by an ICG clearance and a multiple regression equation has been defined retrospectively with postoperative results based on the experience of each surgeon, such as the morbidity or mortality of each patient. In the actual postoperative course of hepatectomized patients, liver insufficiency sometimes occurs unexpectedly even after good pre-operative evaluation of hepatic functional reserve. The pre-operative estimation of hepatic functional reserve by an analysis of the operative results based on the experience of each surgeon can be done only with great uncertainty. In addition, with regard to this point, other crucial factors such as the influences of surgical stress and postoperative management are not considered. If surgeons are too concerned with operative safety and make their evaluation on the basis of these preoperative evaluations alone, the decrease of hepatic functional reserve is apt to be grossly overestimated, with the result that not only will the hepatic resection for liver cancer be incomplete, but also that the cirrhotic patient who is actually resectable will be abandoned as an unresectable case. An infinite capacity for regeneration complicates quantitative assessment of hepatic functional reserve following hepatectomy. Therefore, in order to increase the resectability and radicality of hepatic malignancies, greater efforts should be placed on the total programme of pre-, intra- and postoperative assessment of the metabolic capacity of the remnant liver following hepatectomy.
CHANGES IN THE ENERGETIC METABOLISM FOLLOWING HEPATECTOMY The vital function of the remnant liver essential to survival following hepatectomy depends on the continuous supply of energy produced in mit0ch0ndria.l~ In considering energy metabolism, it is essential to clarify the fundamental nature of the derangement of the energy balance in the remnant liver after hepatectomy. A very convenient expression of this balance is the concept of energy charge (ATP+ 1/2 ADP)/(ATP+ADP+AMP), which is designated by Atkinson as the regulator of the metabolic processes.14Energy charge is a major factor in the regulation of pathways that produce and utilize high-energy phosphate compounds. The energy charge value reflects the cellular energy balance between the energygenerating and energy-utilizing sequences, and is maintained at 0.85-0.90 in normal cells. The regulation of energy generation assures a continuing supply of ATP commensurate with current requirements. In the cells, the mitochondria regenerate ATP at sufficiently rapid rates to maintain a normal energy charge, despite the many enzymatic reactions that utilize ATP. If the energy charge decreases, the ATP-generating sequences are accelerated and the ATP-requiring sequences are slowed down. The energy charge strongly resists any deviation from 0.85, and cellular viability declines with a fall in energy charge. Figure 1 shows the time course of changes in ICG clearance, the ratio of acetoacetate to 3-hydroxybutyrate in arterial blood (KBR), mortality rate, and mitochondria1 phosphorylative activity, energy charge and DNA synthesis of the remnant liver after 70% hepatectomy of rabbits.ls-" The ratio of acetoacetate to 3-hydroxybutyrate (KBR) reflects the ratio of free oxidized: reduced nicotinamide adenine nucleotide in liver mitochondria.18The KBR decreased rapidly to 0.44from 0.93 at 12 h after hepatectomy. Mitochondria1phosphorylative activity increased to 1 7 0 4 ~ of~control, and the energy charge level decreased to 0.767 at 24 h after hepatectomy, after which these values returned to pre-operative levels within 1 week. The mortality rate of hepatectomized rzbbits was highest at 24 h after hepatectomy, when the energy charge levels of
K.Ozawa
298
0
1
2
3 4 5 6 Days after hepatectomy
7 1 4 4 2
Figure 1 Time courses of changes in blood ketone body ratio, ICG clearance, mortality rate, and mitochondrial ATP synthesis, energy charge and DNA synthesis of the remnant liver after 70% hepatectomy of rabbits. Each point represents the mean and standard error of values for six or more animals.
the remnant liver had decreased markedly. During this period of maximum metabolic load, the delicate energy balance in the renmant liver was barely maintained by a compensatory enhancement of mitochondrial phosphorylative activity. Once this stage was passed, however, DNA synthesis was increased concomitantly with the restoration of the energy charge to about 0.80 at 48 h after hepatectomy at which the percentage K of ICG began to increase significantly. Consequently, successful hepatectomy may be said to be a matter of successfully passing through this critical stage. Decreased energy charge may be regarded as one of the most fundamental factors contributing to hepatic failure after major hepatic resection.
The KBR, which is positively correlated with hepatic energy charge, may be regarded as reliable indicator by which to assess the severity of decreased energy charge following hepatectomy. An enhancement in mitochondrial phosphorylative activity of the remnant liver following hepatectomy is the adaptive response of the mitochondria to restore the energy charge in response to a high demand for energy. If the mitochondria cannot produce sufficient ATP to normalize the energy charge, the hepatectomized patient may die of an acute energy crisis. Thus, an analysis of these biochemical events occurring in the mitochondria provides a valuable means of evaluating the potency of the compensatory and regenerative capacity of the liver.
299
Hepatic function and liver resection
EVALUATION OF H E P A T I C FUNCTIONAL R E S E R V E P R I O R T O HEPATECTOMY
loo-. 80
Cytochrome a (+ a3) assay
In cirrhotic liver, the mitochondrial phosphorylative activity cannot be enhanced sufficientlyto overcome the metabolic load imposed on the remnant liver following h e p a t e ~ t o m y . ' ~In - ~the ~ cirrhotic liver, the decrease in mitochondrial phosphorylative activity per unit of respiratory assemblies was negatively correlated with the increase of mitochondrial respiratory enzymes, especially cytochrome a ( + a3),24*28 and positively with the decrease of hepatic energy charge.lg Thus, an increase in cytochrome a( + a3) concentration is one of the most important indices for predicting the decreased functional reserve of cirrhotic patients. Clinically, cirrhotic patients with normal or moderately increased concentrations of cytochrome a( + a3) tolerated major operations well, whereas those with markedly increased cytochrome a( + a3) concentrations had high rates of postoperative morbidity and mo~a~~ty~zz.z~~z~.a~.~~
In our department, a careful assay of cytochrome a( +a3) using about 1g of biopsy material is routinely performed prior to contemplated major hepatic resecti~n.'~As long as the concentrations of cytochrome a( + a3) of motochondria from the remaining liver range from 0.7-1.3 x mol/mg protein, major hepatic resection can be performed without complication or death (Fig. 2). Patients with markedly increased cytochrome a( +a3) concentrations (> 1.5 x mol/mg protein) are less than ideal operative candidates, and the percentage of liver resection should be restricted to less than 40%. Other recent studies from our department have shown that the liver with concentrations of mol/mg procytochrome a( +a3) > 1.5 x tein is associated with severe piecemeal necrosis.33 When the concentration of cytochrome a( + a3) is cO.5 x mol/mg protein, even a supposedly 'minor' operation to remove 20% of the liver should definitely be avoided. Furthermore, based on the observation that the cytochrome c oxidase activity per unit wet weight of liver correlates positively with the amount of cytochrome a( + a3) in mitochondria, we have developed a technically simple and rapid method for the evaluation of
-
-ae& 60-
-
> .C
40a:
0
0.4 0.8 1.2 1.6
2.0
Cytochrome a (+as) concentration (x 10-10 mol/mg protein) Figure 2 Percent of remnant liver and cytochrome a(+a3) concentrations in hepatectomized patients with an uneventful course (0), with postoperative complications ( O ) ,and who died after surgery ( 0 ) .
mitochondrial function by measuring V , or K, of cytochrome c oxidase activity using 10-20 mg needle biopsy material^.^^ Glucose tolerance
In oral glucose tolerance test (GTT), an increase in the hepatic energy charge correlated positively with an increase in the blood glucose, plasma immunoreactive insulin (IRI) levels and the redox potential (NAD+/NADH) of the r n i t o c h ~ n d r i a . ~The ~ - ~possible ~ relationship between phosphorylative activity per unit of cytochrome a( +a3) and glucose tolerance pattern is illustrated in Fig. 3. When the hepatic energy charge is within normal limits, the G T T patterns are parabolic. It is only with the marked decrease of hepatic energy charge that linear G T T patterns develop. These patterns are also reflected in the changes in the phosphorylative activity of the liver mitochondria. In instances in which the phosphorylative activity of liver mitochondria is within normal limits, the parabolic G T T pattern occurs, but when it increases or decreases markedly, the linear G T T patterns develops. Such considerations make it essential to learn more about the changes in glucose tolerance
K. Ozawa
300
/
Decreased
J
NOr ma I
Mitochondr ial phosphorylative activity
I
Normal
(hours)
1
(hours)
Decreased
(hours)
Figure 3 Glucose tolerance curve and hepatic energy charge after an oral glucose load. in hepatectomized patients. G T T could provide at least some prognostic information concerning operative risk, late survival, and the likelihood of early postoperative liver failure in hepatectomized patients. The glucose tolerance of liver cancer patients was principally classified into two groups: the parabolic pattern which tended to exhibit a return of blood glucose level toward normal limits within 120 min (parabolic G T T pattern), and the gradually increasing pattern having no return toward normal limits within 120 min (linear G T T pattern). In addition, it has been found that, even when the G T T pattern is parabolic, hepatic failure easily occurs following hepatectomy when insulin response to a glucose load is suppressed. Measurements of glucose tolerance and plasma insulin level thus enable preoperative separation of patients into four groups with markedly different postoperative prognoses: (i) parabolic G T T pattern with normal or higher insulin secretion; (ii) parabolic G T T pattern with
suppressed insulin secretion (iii) linear G T T pattern with norm1 or higher insulin secretion; and (iv) linear G T T pattern with suppression of insulin ~ e c r e t i o nTherefore, .~~ for successful massive hepatectomy, in addition to the measurement of cytochrome a( + a3) in the remnant liver, it is very important that the patient possesses both a normal or parabolic G T T pattern and a normal insulin secretion from the pancreas after an oral glucose load. Redox tolerance test Glucose tolerance pattern has been found to be closely related to the decrease in hepatic energy charge and the decreasc of redox potential (NAD+/NADH) of liver mitochondria. In this regard, the measurement of the changes in arterial blood ketone body ratio after an oral glucose load, the redox tolerance test (RTT), is useful for evaluating hepatic functional reserve in cirrhotic patients.
301
Hepatic function and liver resection In a study comparing the cumulative enhancement of blood glucose and blood ketone body ratio after an oral glucose load between normal and cirrhotic patients, we found that the AKBR:Aglucose ratio serves as a rapid and accurate indicator for the pre-operative evaluation of the hepatic functional reserve, especially in cirrhotic patients. In 79 hepatectomized patients, the preoperative values of AKBRIA glucose were estimated from the changes in the postoperative blood ketone body ratios (Fig. 4).The values of AKBR/ Aglucose were classified into two groups - group I:> 0.5 ( x and group 11:
