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Significance of glucose tolerance as prognostic sign in hepatectomized patients
Significance of Glucose Tolerance as Prognostic Sign in Hepatectomized Patients Kazue Ozawa, MD, Kyoto, Japan Takeshi Ida, MD, Kyoto, Japan Toshihiko Yamada, MD, Kyoto, Japan lchio Honjo, MD, Kyoto, Japan
It has been found that an enhancement in mitochondrial phosphorylative activity is requisite for later increase in nuclear DNA synthesis in regenerating liver [I] and that such an enhancement is induced with an elevated level of portal factor available to respiratory assemblies [2,3]. The ability of a given patient with cancer of the liver to survive hepatectomy is related to the ability of the mitochondria from the remnant liver to provide sufficient energy required in regenerative processes [4]. A careful measurement of hepatic cytochrome a(+as) as an index of mitochondrial function has regularly been performed b e f ore contemplated major hepatic resection [5]. Although hepatic dysfunction after hepatectomy has been well reported [6-81, there are no widely accepted methods for classifying or describing the changes in functional reserve of the remnant liver after hepatic resection. Recently, it has been found that changes in mitochondrial phosphorylative activity after hepatectomy are closely related to changes in glucose tolerance [9]. Such considerations make it important to learn about changes in glucose tolerance in hepatectomized patients. In this study, interest was focused on the changes in oral glucose tolerance and insulin secretion before and after hepatectomy. Evidence is presented that glucose tolerance test could provide at least some prognostic information concerning operative risk, late survival, and the likelihood of early postoperative liver failure in hepatectomized patients.
primary tumor of the liver. The other two patients had secondary tumors from the stomach. Age of the patients ranged from thirty-two to sixty-three years. There were eleven men and three women. The nonjaundiced patients with gallstone or gastric ulcer were selected as a control. After an overnight fast, the glucose tolerance tests were performed in the conventional manner, with blood samples being taken at fasting and subsequently at regular intervals after the patients ingested 50 gm of glucose. Glucose levels were determined by an o-toluidine method [IO] and serum levels of immunoreactive insulin by radioimmunoassay
[Ill. Results Changes in Glucose Tolerance and Insulin Response in Hepatectomlzed Patients
Case I. A forty-eight year old man was admitted on June 27,1974. Three months before admission he had noted a firm mass in the upper abdomen. The epigastrium protruded forward and the entire abdominal girth was increased. The liver was firmly palpable 7 fingerbreadths below the costal margin on the right and 1 fingerbreadth below the costal margin on the left. The red blood cell count was 395 X lo*, hemoglobin 11.7 gm/lOO ml, hematocrit 36 per cent, serum bilirubin concentration 0.7 mg/lOO ml, and serum glutamic oxalacetic transaminase @GOT) 196
Material and Methods A glucose tolerance test (GTT) was carried out in fourteen patients with cancer of the liver. Twelve patients had From the Department of Surgery, Kyoto University Faculty of Medicine, Kyoto, Japan. This work was supported in part by grants from the Scientific Fund of the Ministry of Education, The Japanese Association for the Study of Metabolism, Miura Scientific Research Fund, and Kyoshin Scientific Research Fund. Reprint requests should be addressed to Kazue Ozawa, MD, Departmsnt of Surgery, Kyoto University Faculty of Medicine, Sakyoku, Kyoto, Japan.
Vofume 131, May 1976
Op.
5
IO
15
20
25
30
DAYS AFTER HEP#TECTOMY Figure 1. Clinical data and laboratory findings in case I.
541
Ozawa et al
2% 3oc YE k# 0 15( 0 3 (3 Q lO( 8 ii! 5(
I
I
I
I
I
I
I
30 60 90 120 I50 180 0 MINUTES AFTER GLUCOSE LOAD
J
Figure 2. Changes in Gm in case I. Number in figure indicates the days afler hepatectomy.
mu/ml. On May 21, 1974, a large tumor involving nearly all the right lobe of the liver was found at laparotomy. Considering that the concentration of cytochrome a(+as) was 7.91 mpM/gm of wet weight of liver in comparison with approximately 4.5 mwM/gm in normal human liver, we recommended and performed extended right hepatectomy [5]. The postoperative course was uneventful. The operative specimen weight was 1,170 gm. Histologically, the mass was a hepatoma. The clinical data are described in Figure 1. Serum bilirubin level increased immediately after operation but then decreased and after seven days it was almost within normal limits. SGOT showed a similar marked increase but afterward declined more quickly toward, but not quite to, normal limits. In preoperative GTT (dotted line in Figure 2), the blood glucose curve was a parabolic pattern having the peak of 220 mg/dl at 60 minutes after a glucose load. The insulin secretion from the pancreas after a glucose load was significantly greater than that of controls. (Table I, Figure 3.) On the fourth postoperative day, the blood glucose level was about 200 mg/dl, even at 120 minutes after a glucose load, and the plasma insulin level showed the maximum of 100 pU/ml at 120 minutes. On the tenth and sixteenth postoperative days, the blood glucose and plasma insulin levels were the maximum at 60 minutes and considerably greater than those in controls. On the twenty-eighth postoperative day, the blood glucose and the plasma insulin levels recovered to almost within normal limits. Case II. A thirty-seven year old man was admitted on May l&1970. Two months before admission, he had epigastric pain and noticed the protrusion of right hypochondrium. The liver was firmly palpable 4 fingerbreadths below the costal arch. The red blood cell count was 486 x 104, hemoglobin 96 per cent (Sahli), hematocrit 46 per cent, serum bilirubin within normal limits, SGOT 66 Karmen units, serum pyruvic oxalacetic transaminase (SGPT) 91 Karmen units, and alkaline phosphatase 39 KingArmstrong units. Angiography revealed a massive type of tumor in the right lobe. Extended right hepatectomy was done. The operative specimen weight was 1,300 gm. Histologically, the mass in the liver was hepatoma with liver cirrhosis. On the first postoperative day, levels of SGOT and total bilirubin were elevated but rapidly declined within six days to within normal limits. Subsequently, these two levels increased gradually and the patient died of hepatic insufficiency on the thirty-first postoperative day. The clinical data and changes in GTT are described in Figure 4. In preoperative GTT, the blood glucose level increased gradually until 2 hours after the glucose load. In the GTT pattern after extended right hepatectomy, the blood glucose level showed no return toward normal limits within 3 hours. The pattern is in striking contrast to that of case I.
Figure 3. Changes in insulin response after a glucose load in case I. Number in figure indicates the days after hepatectomy.
542
Case III. A sixty-three year old woman was admitted on June l&1974. Three months before admission, she had had a slight pain in the right hypochondrium. The liver was palpable 4 fingerbreadths below the costal arch. The red blood cell count was 328 X 104, hemoglobin 9.2 gm/dl(57
The American Journal of Surgery
Glucose Tolerance and Hepatectomy
TABLE I Serum IRI Level during Preoperative GTT in Patients in Cases I and III Time (min)
Case
(8 patients)
I
15.1 + 1.8 25
Case I I I Note:
8 All values expressed
30
15
0 Control
30.6
5 5.4
as mean r standard
* 9.5
57.2
81 27
46 18 error
39.8
f 6.2 99 28
35.8
+ 9.8 74
...
180
120
90
60
31.2
+ 8.0 40 40
28.5
f. 8.4
‘id
in pU/ml.
Figure 4. dZhk8g&q in iaboratory findings and GlTpettern afler hepatectomy in case ii.
Figure 5. Chadges in laboratory findings, GTTpattern, and insulin response atYef hepatectbmy in case iii. per cent), hematocrit 27 per cent, serum bilirubin concentration 0.9 mg/106 ml, and level of SGOT 101 mU/dl. Angiography revealed a massive tumor in the right lobe. On July 7, 1974, operative exploration confirmed the presence of two separate masses of hepatoma and cholangiocarcinoma in the right lobe, as shown in Figure 5. Only hepatoma (380 gm) was removed because of difficulty of separation of white mass (cholangiocarcinoma) from vena cava. There was about 200 ml of ascites. No stigmata of cirrhosis were evident. She had remained well for the first
Vohmw 131, May 1676
seven days postoperatively. On the eighth postoperative day, she took 5 mg of nitrazepam (Benzalin, Hoffmann-La Roche & Co, Ltd) as sedative. She developed muscle weakness and disturbance of movement of leg and arm for three days. At the same time, ascites and straw-colored fluid in the thorax accumulated, and massive fresh bleeding per rectum continued. She died of the bleeding on the thirty-first postoperative day. In preoperative GTT, the blood glucose curve showed the parabolic, pattern having a peak of 200 mg/dl at 60 minutes after a glucose load. The
543
Ozawa et al
findings, and GTT pattern in the patients with liver cancer. The patients with parabolic GTT pattern fared relatively better than did those with linear GTT pattern. However, in liver function tests performed just before their glucose tolerance tests, such as serum albumin, SGOT, SGPT, lactic dehydrogenase, and serum bilirubin, there were no significant differences between patients with parabolic GTT pattern and those with linear GTT pattern.
insulin Sretion after a glucose load was greatly depressed. (Table I.) On the fourth postoperativk day, the blood glucose level after a glucose load increased gtadually and the plasma insulin level was depressed severely. On the ninth poStoperative day when she took Renzalin, the blood glucose level increased to greater than 300 mg/dl after a glucose load and the plasma insulin level remained unchanged. PrognostIc Evaluation by Glucose Tolerance in Patients with Lliref Cancer
The glucose tolerance of the patients with cancer of the liver was principally classified into two groups; the parabolic pattern having somewhat of a return of.blood glucose level toward normal limits within 120 minutes (parabolic GTT pattern) and the gradually increasing pattern having no return toward normal limits within 120 minutes (linear GTT pattern). Figures 6 and 7 show the clinical data, laboratory
Ccx age
and
Primary
disease
Type
zf
b
43
K
It.
xii
findings Aib
iP
CO?
Ilh
103
h
:ateral
Course
after
CTT
;77
p?tter”
portal
hepatoma
; t. 5Y H
of
Experimentally, it has been found that in the jaundiced animals the degree of glucose intolerance is correlated with the severity of derangement of liver mitochondrial metabolism [12,13]. The phosphorjilative Activity in liver mitochondria of jaundiced rats with parabolic GTT pattern was always greater
laboratory
surgery
:igation branch
Comments
Llc
6 months
scgmentectomy
Laatrlc cancer with liver meta-
Y
E
h
5
Llcd
4 months
200
I
atas1s
#IL laterai SegnTenteCtOmy It. t11gat1on of rt. portal branch
43
K
v.etastat1c 11ver cancer (orlgln r.0 clear)
b
h
h
_
-
-
it.
41
n
h
Hepatoma
200 died
9.4
mar.tbs loo
lateral
40
F
N
caatr1c cancer rlth liver nctastasis
Lt.
49
n
segmentectomy
Hepatoma clrrhosls
rlth
lateral
-
N
N
scgnwntectomy
265
Figure 6. PIimary disease, type of surgery, and glucose tolerance in patients with parabolic G7Tpattems. N = within normal iimits,accordi~g to the following definition: total biiirubin ( 8) < 1.0 mg/lOO ml; blood urea nitrogen (BUN) <20 mg/lOO ml; serum albumin (A/b) > 3.5 gm/lOO ml; serum alkaline phosphatase ( AP) < 80 munits/mi; serum giutamic oxaiacetic transaminase (GOT)
544
The American
Journal
01 Surgery
Glucose Tolerance and Hepatectomy
than that in liver deprived of endogenous insulin through portal blood whereas that in jaundiced rabbits with linear GTT pattern was less than in insulin-deprived liver tissue. Of particular interest was the fact that the linear GYM’ patterns were associated with a high mortality rate and have been referred to as poor prognostic signs. However, it has typically been found in the hepatectomized rabbits that a sequence of characteristic changes in glucose tolerance parallel changes in mitochondrial phosphorylative activity [9]. At an early stage of the regenerative process when phosphorylative activity in the mitochondria from the remnant liver was enhanced considerably more than that in controls, the GTT patterns show the plateau curve with hypoglycemia and then the linear GTT curve. Afterward, when mitochondrial function returned gradually to normal level, the GTT pattern returned toward normal patterns. Such changes occurring after hepatectomy is presumably a purposeful metabolic reaction tending to maintain the delicate balance of energy metabolism in the regenerating liver. Restoration of glucose intolerance to normal limits suggests the metabolic reserve in the mitochondria of the liver remnant. On the contrary, both the plateau pattern
Type
of
surgery
with hypoglycemia and the linear pattern with marked late return toward normal in GTT are indicative of a marked enhancement of mitochondrial phosphorylative activity before an increase in nuclear DNA synthesis. This period appears to be the time when the metabolic overload is maximally imposed upon the remnant liver, and the delicate balance for energy generation in the remnant liver is barely maintained by a compensatory enhancement of mitochondrial phosphorylative activity. In addition, it has been found that the hepatectomized animals with shorter periods of plateau or linear GTT pattern have remarkably greater regenerative and restorative power of the liver after major hepatic resection than those with longer periods [9]. Such a series of changes in glucose tolerance after partial hepatectomy was observed in a hepatectomized patient with blunt trauma [9]. In this patient the linear GTT pattern continued for a longer period than that in hepatectomized rabbits. However, in the patient in case I, the linear GTT pattern was not observed during the time tested after the extended right hepatectomy. These results indicate that the remnant liver passed through an early, energy-requiring stage of the regenerative process already at
Laboratory B
findings
C.,ur~e
BUN
*lb
AP
GOT
LD”
2.6
N
3.2
N
130
-
Ti
N
,.o
250
105
500
3.1
N
3.0
219
263
213
2.0
-
1.3
25
Exploration only + chemotherapy by infualon through hepatic artery 46 M
Hepatoma
51 El
Cholangiona
Exploration
after
CTT
GTT pattern
Died of hepatorenal fallure.hepatoancephalopathy and C.I. bleeding 15 days after CTT2
only died
3 montha
Died
19
2 months
NO 1aparotow 52
F
“epatoma cirrhosis
with
confirmed Exploration 32
M
days
after
CTT2
by angiography only
fiepatoma
2.1
216
261
263
Died
N
250
250
420
M;th;f
Gxploration only+ c?emot?eFapy,py infusion Hepatoma cirrhosis
with
hepatic
coma
1.5
Figure 7. Wmaty disease, type of surgery, and glucose tolerance in patlents with linear GTT patterns.N = with/n normal Mmfts according to the followkfg definition: total bilirubin (B) < 1.0 mg/lOO ml; blood urea nlbvgen (BUN) <20 mg/lOO ml; serum atbumln ( AB) > 3.5 gm/lOO ml; setwm alkaline phasphatase AP) < 80 munits/ml; serum gtutamic oxalacetic transamk#ase ( GGT) < 50 munlts/ml; and lactic dehydrogenase ( LDH) < 200 nwnits/ml.
(
va&lma131,Yayi1976
545
Ozawa et al
the time of operation. Consequently, removal of the right and middle lobes involves only a relatively small loss in terms of metabolic function. This is supported by the fact that the remnant liver markedly hypertrophied and the remnant liver had an increased concentration of respiratory enzymes as an adaptive mechanism in aerobic mechanism. However, in the patient with a linear GTT pattern in case II, it can be suggested that the delicate energy balance of the remaining liver was barely maintained even during the preoperative period and the mitochondria in the remnant liver could not provide sufficient energy at an early stage of the regenerative process. From these results it seems likely that success of major hepatic resection depends on whether or not the remaining liver has already passed through the early, energyrequiring process at the time of hepatectomy. These seem consistent with the fact that the patients with linear GTT patterns had a short life expectancy. It has been found that insulin plays an important role in the mechanism by which portal blood controls oxidative phosphorylation of the liver mitochondria [14,15]. In the patient in case III, the blood glucose level showed a parabolic GTT pattern but the plasma insulin level after the glucose load was severely suppressed in comparison with that of controls. On the fourth postoperative day, the glucose level showed the linear GTT pattern and the plasma insulin level was severely inhibited. Although a more complex mechanism is involved in producing the longstanding hyperglycemia and insulin suppression, the linear GTT pattern was highly intensified with Benzalin. These indicate that, when insulin response to a glucose load is suppressed even if the parabolic GTT pattern presents, hepatic failure may be easily induced in a posthepatectomic period even with commonly used medicaments. From the results reported herein, measurement of glucose tolerance and plasma insulin level enables preoperative separation of patients into three groups with markedly different probabilities of operative survival: (1) the parabolic GTT pattern with normal or higher insulin secretion, (2) the parabolic GTT pattern with suppressed insulin secretion, and (3) the linear GTT pattern. In addition to the measurements of cytochrome a(+as) in the remnant liver [5], it is very important in successful massive hepatectomy that the patients have both a normal or parabolic GTT pattern and normal insulin secretion from the pancreas after a glucose load. If these concepts are supported by further observations and studies, the use of GTT will be essential for the prediction of operative prognosis, better than any other currently used index of liver function.
546
Summary
Glucose tolerance was determined in fourteen patients with cancer of the liver. The patients with parabolic GTT patterns fared relatively better than did those with linear GTT patterns. In the patients with successful extended right hepatectomy, gradually increasing and long-standing hyperglycemia (linear GTT pattern) in response to an oral glucose load was not observed after hepatectomy and the insulin response was significantly greater than that in controls. However, in the patient with unsuccessful extended right hepatectomy , the linear GTT pattern continued for a more prolonged period after hepatectomy.
References 1.
2.
YamaokaY.OhsawaT, TakasanH,Ozawa
K. Honjo I: Energy requirement in regenerative and atrophic processes of the liver in man and other mammals. Sure Obstet 139: _ Gynecol _ 234, 1974. Ozawa K, Kitamura 0, Yamaoka Y, Mizukami T, Kamano T, Takeda H. Takasan l-i. Honio I: Role of oortal blood on the enhancement of liver mitoc’hondrialmetabolism. Am J Surg 124: 16, 1972. Ozawa K, Kitamura 0, Yamaoka Y, Nambu H, Honjo I: Phosphorylative capacity of liver mitochondria with an elevated ratio of cytochrome ci-CI to cytochrome a(+a3). J /_a6 C/in Meda3: 97, 1974. Ozawa K, Honjo I: Control of phosphorylative activity in human liver mitochrondria through changes in respiratory enzyme levels. C/in Sci Mel A-fed48: 1975. Ozawa K, Yamaoka Y, Kitamura 0, Nambu H, Kamiyama Y. Takeda H, Takasan H. Honjo I: Clinical application of cytochrome a(+as) assay of mitochondria from liver specimens: an aid in determining metabolic tolerance of liver remnant for hepatic resection. Ann Surg 160: 666, 1974. Aronson KF, Ericsson B, Pihl B: Metabolic changes following major hepatic resection. Ann Surg 169: 102. 1969. AlmersjS 0, Bengmark S, Hafstrijm LO, Olsson R: Enzyme and function changes after extensive liver resection in man. Ann Surg 169: 111, 1969. Lin T. Chen C: Metabolic function and regeneration of cirrhotic and non-cirrhotic livers after hepatic lobectomy in man. Ann Surg 162: 959, 1965. Ida T, Ozawa K, Honjo I: Glucose intolerance after massive liver resection in man and other mammals. Am J Surg 129: 523. 1975. Hultman E: Rapid specific method for determination of aldosaccharides in bodv fluids. Nature 183: 106, 1959. Hales CN, Randle PJ! Immunoassay of insulin with insulinantibody precipitate. Biochem J 66: 137, 1963. Yamada T, Ida T, Yamaoka Y, Ozawa K, Takasan H, Honjo I: Two distinct patterns of glucose intolerance in icteric rats and rabbits. and their relations to impaired function of liver mitochondria. J Lab C/in bled (In press.) Ozawa K, Ida T, Yamada T. Yamaoka Y, Takasan H, Honjo I: Oral glucose tolerance in jaundiced patients. Surg Gynecol Obsfef (In press.) Ozawa K, Yamaoka Y, Nambu H, Honjo I: Insulin as the primary factor governing changes of mitochondrial metabolism leading to liver regeneration and atrophy. Am J Surg 127: 669, 1974. Ozawa K. Yamada T, Honjo I: Role of insulin as a portal factor in maintaining the viability of liver. Ann Surg 160: 716, 1974. r
3.
4.
5.
6. 7.
6.
9.
IO. Il. 12.
13.
14.
15.
The American Journal 01 Surgery
It has been found that an enhancement in mitochondrial phosphorylative activity is requisite for later increase in nuclear DNA synthesis in regenerating liver [I] and that such an enhancement is induced with an elevated level of portal factor available to respiratory assemblies [2,3]. The ability of a given patient with cancer of the liver to survive hepatectomy is related to the ability of the mitochondria from the remnant liver to provide sufficient energy required in regenerative processes [4]. A careful measurement of hepatic cytochrome a(+as) as an index of mitochondrial function has regularly been performed b e f ore contemplated major hepatic resection [5]. Although hepatic dysfunction after hepatectomy has been well reported [6-81, there are no widely accepted methods for classifying or describing the changes in functional reserve of the remnant liver after hepatic resection. Recently, it has been found that changes in mitochondrial phosphorylative activity after hepatectomy are closely related to changes in glucose tolerance [9]. Such considerations make it important to learn about changes in glucose tolerance in hepatectomized patients. In this study, interest was focused on the changes in oral glucose tolerance and insulin secretion before and after hepatectomy. Evidence is presented that glucose tolerance test could provide at least some prognostic information concerning operative risk, late survival, and the likelihood of early postoperative liver failure in hepatectomized patients.
primary tumor of the liver. The other two patients had secondary tumors from the stomach. Age of the patients ranged from thirty-two to sixty-three years. There were eleven men and three women. The nonjaundiced patients with gallstone or gastric ulcer were selected as a control. After an overnight fast, the glucose tolerance tests were performed in the conventional manner, with blood samples being taken at fasting and subsequently at regular intervals after the patients ingested 50 gm of glucose. Glucose levels were determined by an o-toluidine method [IO] and serum levels of immunoreactive insulin by radioimmunoassay
[Ill. Results Changes in Glucose Tolerance and Insulin Response in Hepatectomlzed Patients
Case I. A forty-eight year old man was admitted on June 27,1974. Three months before admission he had noted a firm mass in the upper abdomen. The epigastrium protruded forward and the entire abdominal girth was increased. The liver was firmly palpable 7 fingerbreadths below the costal margin on the right and 1 fingerbreadth below the costal margin on the left. The red blood cell count was 395 X lo*, hemoglobin 11.7 gm/lOO ml, hematocrit 36 per cent, serum bilirubin concentration 0.7 mg/lOO ml, and serum glutamic oxalacetic transaminase @GOT) 196
Material and Methods A glucose tolerance test (GTT) was carried out in fourteen patients with cancer of the liver. Twelve patients had From the Department of Surgery, Kyoto University Faculty of Medicine, Kyoto, Japan. This work was supported in part by grants from the Scientific Fund of the Ministry of Education, The Japanese Association for the Study of Metabolism, Miura Scientific Research Fund, and Kyoshin Scientific Research Fund. Reprint requests should be addressed to Kazue Ozawa, MD, Departmsnt of Surgery, Kyoto University Faculty of Medicine, Sakyoku, Kyoto, Japan.
Vofume 131, May 1976
Op.
5
IO
15
20
25
30
DAYS AFTER HEP#TECTOMY Figure 1. Clinical data and laboratory findings in case I.
541
Ozawa et al
2% 3oc YE k# 0 15( 0 3 (3 Q lO( 8 ii! 5(
I
I
I
I
I
I
I
30 60 90 120 I50 180 0 MINUTES AFTER GLUCOSE LOAD
J
Figure 2. Changes in Gm in case I. Number in figure indicates the days afler hepatectomy.
mu/ml. On May 21, 1974, a large tumor involving nearly all the right lobe of the liver was found at laparotomy. Considering that the concentration of cytochrome a(+as) was 7.91 mpM/gm of wet weight of liver in comparison with approximately 4.5 mwM/gm in normal human liver, we recommended and performed extended right hepatectomy [5]. The postoperative course was uneventful. The operative specimen weight was 1,170 gm. Histologically, the mass was a hepatoma. The clinical data are described in Figure 1. Serum bilirubin level increased immediately after operation but then decreased and after seven days it was almost within normal limits. SGOT showed a similar marked increase but afterward declined more quickly toward, but not quite to, normal limits. In preoperative GTT (dotted line in Figure 2), the blood glucose curve was a parabolic pattern having the peak of 220 mg/dl at 60 minutes after a glucose load. The insulin secretion from the pancreas after a glucose load was significantly greater than that of controls. (Table I, Figure 3.) On the fourth postoperative day, the blood glucose level was about 200 mg/dl, even at 120 minutes after a glucose load, and the plasma insulin level showed the maximum of 100 pU/ml at 120 minutes. On the tenth and sixteenth postoperative days, the blood glucose and plasma insulin levels were the maximum at 60 minutes and considerably greater than those in controls. On the twenty-eighth postoperative day, the blood glucose and the plasma insulin levels recovered to almost within normal limits. Case II. A thirty-seven year old man was admitted on May l&1970. Two months before admission, he had epigastric pain and noticed the protrusion of right hypochondrium. The liver was firmly palpable 4 fingerbreadths below the costal arch. The red blood cell count was 486 x 104, hemoglobin 96 per cent (Sahli), hematocrit 46 per cent, serum bilirubin within normal limits, SGOT 66 Karmen units, serum pyruvic oxalacetic transaminase (SGPT) 91 Karmen units, and alkaline phosphatase 39 KingArmstrong units. Angiography revealed a massive type of tumor in the right lobe. Extended right hepatectomy was done. The operative specimen weight was 1,300 gm. Histologically, the mass in the liver was hepatoma with liver cirrhosis. On the first postoperative day, levels of SGOT and total bilirubin were elevated but rapidly declined within six days to within normal limits. Subsequently, these two levels increased gradually and the patient died of hepatic insufficiency on the thirty-first postoperative day. The clinical data and changes in GTT are described in Figure 4. In preoperative GTT, the blood glucose level increased gradually until 2 hours after the glucose load. In the GTT pattern after extended right hepatectomy, the blood glucose level showed no return toward normal limits within 3 hours. The pattern is in striking contrast to that of case I.
Figure 3. Changes in insulin response after a glucose load in case I. Number in figure indicates the days after hepatectomy.
542
Case III. A sixty-three year old woman was admitted on June l&1974. Three months before admission, she had had a slight pain in the right hypochondrium. The liver was palpable 4 fingerbreadths below the costal arch. The red blood cell count was 328 X 104, hemoglobin 9.2 gm/dl(57
The American Journal of Surgery
Glucose Tolerance and Hepatectomy
TABLE I Serum IRI Level during Preoperative GTT in Patients in Cases I and III Time (min)
Case
(8 patients)
I
15.1 + 1.8 25
Case I I I Note:
8 All values expressed
30
15
0 Control
30.6
5 5.4
as mean r standard
* 9.5
57.2
81 27
46 18 error
39.8
f 6.2 99 28
35.8
+ 9.8 74
...
180
120
90
60
31.2
+ 8.0 40 40
28.5
f. 8.4
‘id
in pU/ml.
Figure 4. dZhk8g&q in iaboratory findings and GlTpettern afler hepatectomy in case ii.
Figure 5. Chadges in laboratory findings, GTTpattern, and insulin response atYef hepatectbmy in case iii. per cent), hematocrit 27 per cent, serum bilirubin concentration 0.9 mg/106 ml, and level of SGOT 101 mU/dl. Angiography revealed a massive tumor in the right lobe. On July 7, 1974, operative exploration confirmed the presence of two separate masses of hepatoma and cholangiocarcinoma in the right lobe, as shown in Figure 5. Only hepatoma (380 gm) was removed because of difficulty of separation of white mass (cholangiocarcinoma) from vena cava. There was about 200 ml of ascites. No stigmata of cirrhosis were evident. She had remained well for the first
Vohmw 131, May 1676
seven days postoperatively. On the eighth postoperative day, she took 5 mg of nitrazepam (Benzalin, Hoffmann-La Roche & Co, Ltd) as sedative. She developed muscle weakness and disturbance of movement of leg and arm for three days. At the same time, ascites and straw-colored fluid in the thorax accumulated, and massive fresh bleeding per rectum continued. She died of the bleeding on the thirty-first postoperative day. In preoperative GTT, the blood glucose curve showed the parabolic, pattern having a peak of 200 mg/dl at 60 minutes after a glucose load. The
543
Ozawa et al
findings, and GTT pattern in the patients with liver cancer. The patients with parabolic GTT pattern fared relatively better than did those with linear GTT pattern. However, in liver function tests performed just before their glucose tolerance tests, such as serum albumin, SGOT, SGPT, lactic dehydrogenase, and serum bilirubin, there were no significant differences between patients with parabolic GTT pattern and those with linear GTT pattern.
insulin Sretion after a glucose load was greatly depressed. (Table I.) On the fourth postoperativk day, the blood glucose level after a glucose load increased gtadually and the plasma insulin level was depressed severely. On the ninth poStoperative day when she took Renzalin, the blood glucose level increased to greater than 300 mg/dl after a glucose load and the plasma insulin level remained unchanged. PrognostIc Evaluation by Glucose Tolerance in Patients with Lliref Cancer
The glucose tolerance of the patients with cancer of the liver was principally classified into two groups; the parabolic pattern having somewhat of a return of.blood glucose level toward normal limits within 120 minutes (parabolic GTT pattern) and the gradually increasing pattern having no return toward normal limits within 120 minutes (linear GTT pattern). Figures 6 and 7 show the clinical data, laboratory
Ccx age
and
Primary
disease
Type
zf
b
43
K
It.
xii
findings Aib
iP
CO?
Ilh
103
h
:ateral
Course
after
CTT
;77
p?tter”
portal
hepatoma
; t. 5Y H
of
Experimentally, it has been found that in the jaundiced animals the degree of glucose intolerance is correlated with the severity of derangement of liver mitochondrial metabolism [12,13]. The phosphorjilative Activity in liver mitochondria of jaundiced rats with parabolic GTT pattern was always greater
laboratory
surgery
:igation branch
Comments
Llc
6 months
scgmentectomy
Laatrlc cancer with liver meta-
Y
E
h
5
Llcd
4 months
200
I
atas1s
#IL laterai SegnTenteCtOmy It. t11gat1on of rt. portal branch
43
K
v.etastat1c 11ver cancer (orlgln r.0 clear)
b
h
h
_
-
-
it.
41
n
h
Hepatoma
200 died
9.4
mar.tbs loo
lateral
40
F
N
caatr1c cancer rlth liver nctastasis
Lt.
49
n
segmentectomy
Hepatoma clrrhosls
rlth
lateral
-
N
N
scgnwntectomy
265
Figure 6. PIimary disease, type of surgery, and glucose tolerance in patients with parabolic G7Tpattems. N = within normal iimits,accordi~g to the following definition: total biiirubin ( 8) < 1.0 mg/lOO ml; blood urea nitrogen (BUN) <20 mg/lOO ml; serum albumin (A/b) > 3.5 gm/lOO ml; serum alkaline phosphatase ( AP) < 80 munits/mi; serum giutamic oxaiacetic transaminase (GOT)
544
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01 Surgery
Glucose Tolerance and Hepatectomy
than that in liver deprived of endogenous insulin through portal blood whereas that in jaundiced rabbits with linear GTT pattern was less than in insulin-deprived liver tissue. Of particular interest was the fact that the linear GYM’ patterns were associated with a high mortality rate and have been referred to as poor prognostic signs. However, it has typically been found in the hepatectomized rabbits that a sequence of characteristic changes in glucose tolerance parallel changes in mitochondrial phosphorylative activity [9]. At an early stage of the regenerative process when phosphorylative activity in the mitochondria from the remnant liver was enhanced considerably more than that in controls, the GTT patterns show the plateau curve with hypoglycemia and then the linear GTT curve. Afterward, when mitochondrial function returned gradually to normal level, the GTT pattern returned toward normal patterns. Such changes occurring after hepatectomy is presumably a purposeful metabolic reaction tending to maintain the delicate balance of energy metabolism in the regenerating liver. Restoration of glucose intolerance to normal limits suggests the metabolic reserve in the mitochondria of the liver remnant. On the contrary, both the plateau pattern
Type
of
surgery
with hypoglycemia and the linear pattern with marked late return toward normal in GTT are indicative of a marked enhancement of mitochondrial phosphorylative activity before an increase in nuclear DNA synthesis. This period appears to be the time when the metabolic overload is maximally imposed upon the remnant liver, and the delicate balance for energy generation in the remnant liver is barely maintained by a compensatory enhancement of mitochondrial phosphorylative activity. In addition, it has been found that the hepatectomized animals with shorter periods of plateau or linear GTT pattern have remarkably greater regenerative and restorative power of the liver after major hepatic resection than those with longer periods [9]. Such a series of changes in glucose tolerance after partial hepatectomy was observed in a hepatectomized patient with blunt trauma [9]. In this patient the linear GTT pattern continued for a longer period than that in hepatectomized rabbits. However, in the patient in case I, the linear GTT pattern was not observed during the time tested after the extended right hepatectomy. These results indicate that the remnant liver passed through an early, energy-requiring stage of the regenerative process already at
Laboratory B
findings
C.,ur~e
BUN
*lb
AP
GOT
LD”
2.6
N
3.2
N
130
-
Ti
N
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250
105
500
3.1
N
3.0
219
263
213
2.0
-
1.3
25
Exploration only + chemotherapy by infualon through hepatic artery 46 M
Hepatoma
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after
CTT
GTT pattern
Died of hepatorenal fallure.hepatoancephalopathy and C.I. bleeding 15 days after CTT2
only died
3 montha
Died
19
2 months
NO 1aparotow 52
F
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with
confirmed Exploration 32
M
days
after
CTT2
by angiography only
fiepatoma
2.1
216
261
263
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N
250
250
420
M;th;f
Gxploration only+ c?emot?eFapy,py infusion Hepatoma cirrhosis
with
hepatic
coma
1.5
Figure 7. Wmaty disease, type of surgery, and glucose tolerance in patlents with linear GTT patterns.N = with/n normal Mmfts according to the followkfg definition: total bilirubin (B) < 1.0 mg/lOO ml; blood urea nlbvgen (BUN) <20 mg/lOO ml; serum atbumln ( AB) > 3.5 gm/lOO ml; setwm alkaline phasphatase AP) < 80 munits/ml; serum gtutamic oxalacetic transamk#ase ( GGT) < 50 munlts/ml; and lactic dehydrogenase ( LDH) < 200 nwnits/ml.
(
va&lma131,Yayi1976
545
Ozawa et al
the time of operation. Consequently, removal of the right and middle lobes involves only a relatively small loss in terms of metabolic function. This is supported by the fact that the remnant liver markedly hypertrophied and the remnant liver had an increased concentration of respiratory enzymes as an adaptive mechanism in aerobic mechanism. However, in the patient with a linear GTT pattern in case II, it can be suggested that the delicate energy balance of the remaining liver was barely maintained even during the preoperative period and the mitochondria in the remnant liver could not provide sufficient energy at an early stage of the regenerative process. From these results it seems likely that success of major hepatic resection depends on whether or not the remaining liver has already passed through the early, energyrequiring process at the time of hepatectomy. These seem consistent with the fact that the patients with linear GTT patterns had a short life expectancy. It has been found that insulin plays an important role in the mechanism by which portal blood controls oxidative phosphorylation of the liver mitochondria [14,15]. In the patient in case III, the blood glucose level showed a parabolic GTT pattern but the plasma insulin level after the glucose load was severely suppressed in comparison with that of controls. On the fourth postoperative day, the glucose level showed the linear GTT pattern and the plasma insulin level was severely inhibited. Although a more complex mechanism is involved in producing the longstanding hyperglycemia and insulin suppression, the linear GTT pattern was highly intensified with Benzalin. These indicate that, when insulin response to a glucose load is suppressed even if the parabolic GTT pattern presents, hepatic failure may be easily induced in a posthepatectomic period even with commonly used medicaments. From the results reported herein, measurement of glucose tolerance and plasma insulin level enables preoperative separation of patients into three groups with markedly different probabilities of operative survival: (1) the parabolic GTT pattern with normal or higher insulin secretion, (2) the parabolic GTT pattern with suppressed insulin secretion, and (3) the linear GTT pattern. In addition to the measurements of cytochrome a(+as) in the remnant liver [5], it is very important in successful massive hepatectomy that the patients have both a normal or parabolic GTT pattern and normal insulin secretion from the pancreas after a glucose load. If these concepts are supported by further observations and studies, the use of GTT will be essential for the prediction of operative prognosis, better than any other currently used index of liver function.
546
Summary
Glucose tolerance was determined in fourteen patients with cancer of the liver. The patients with parabolic GTT patterns fared relatively better than did those with linear GTT patterns. In the patients with successful extended right hepatectomy, gradually increasing and long-standing hyperglycemia (linear GTT pattern) in response to an oral glucose load was not observed after hepatectomy and the insulin response was significantly greater than that in controls. However, in the patient with unsuccessful extended right hepatectomy , the linear GTT pattern continued for a more prolonged period after hepatectomy.
References 1.
2.
YamaokaY.OhsawaT, TakasanH,Ozawa
K. Honjo I: Energy requirement in regenerative and atrophic processes of the liver in man and other mammals. Sure Obstet 139: _ Gynecol _ 234, 1974. Ozawa K, Kitamura 0, Yamaoka Y, Mizukami T, Kamano T, Takeda H. Takasan l-i. Honio I: Role of oortal blood on the enhancement of liver mitoc’hondrialmetabolism. Am J Surg 124: 16, 1972. Ozawa K, Kitamura 0, Yamaoka Y, Nambu H, Honjo I: Phosphorylative capacity of liver mitochondria with an elevated ratio of cytochrome ci-CI to cytochrome a(+a3). J /_a6 C/in Meda3: 97, 1974. Ozawa K, Honjo I: Control of phosphorylative activity in human liver mitochrondria through changes in respiratory enzyme levels. C/in Sci Mel A-fed48: 1975. Ozawa K, Yamaoka Y, Kitamura 0, Nambu H, Kamiyama Y. Takeda H, Takasan H. Honjo I: Clinical application of cytochrome a(+as) assay of mitochondria from liver specimens: an aid in determining metabolic tolerance of liver remnant for hepatic resection. Ann Surg 160: 666, 1974. Aronson KF, Ericsson B, Pihl B: Metabolic changes following major hepatic resection. Ann Surg 169: 102. 1969. AlmersjS 0, Bengmark S, Hafstrijm LO, Olsson R: Enzyme and function changes after extensive liver resection in man. Ann Surg 169: 111, 1969. Lin T. Chen C: Metabolic function and regeneration of cirrhotic and non-cirrhotic livers after hepatic lobectomy in man. Ann Surg 162: 959, 1965. Ida T, Ozawa K, Honjo I: Glucose intolerance after massive liver resection in man and other mammals. Am J Surg 129: 523. 1975. Hultman E: Rapid specific method for determination of aldosaccharides in bodv fluids. Nature 183: 106, 1959. Hales CN, Randle PJ! Immunoassay of insulin with insulinantibody precipitate. Biochem J 66: 137, 1963. Yamada T, Ida T, Yamaoka Y, Ozawa K, Takasan H, Honjo I: Two distinct patterns of glucose intolerance in icteric rats and rabbits. and their relations to impaired function of liver mitochondria. J Lab C/in bled (In press.) Ozawa K, Ida T, Yamada T. Yamaoka Y, Takasan H, Honjo I: Oral glucose tolerance in jaundiced patients. Surg Gynecol Obsfef (In press.) Ozawa K, Yamaoka Y, Nambu H, Honjo I: Insulin as the primary factor governing changes of mitochondrial metabolism leading to liver regeneration and atrophy. Am J Surg 127: 669, 1974. Ozawa K. Yamada T, Honjo I: Role of insulin as a portal factor in maintaining the viability of liver. Ann Surg 160: 716, 1974. r
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The American Journal 01 Surgery