BESSHO, HIDEAKI

KANAZAWA, HIDETAKA

KAWAMURA, MASAO

KUYAMA, TAKESHI

MIYAMOTO, MASAAKI

SHIMOTO, TAKASHI

SUDO, TAKAAKI

UCHIDA, TAKAHISA

YASUDA, CHIKAO

Kyoto University Research Information Repository

Title Effect of Glucagon on Bile Acid Metabolism after Resection ofLiver Cancer in Patients with CirrhosisAuthor(s)SUDO, TAKAAKI; BESSHO, HIDEAKI; MIYAMOTO,MASAAKI; KANAZAWA, HIDETAKA; YASUDA,CHIKAO; UCHIDA, TAKAHISA; KAWAMURA, MASAO;SHIMOTO, TAKASHI; KUYAMA, TAKESHICitation日本外科宝函 (1990), 59(3): 217-223Issue Date1990-05-01URL http://hdl.handle.net/2433/204449RightType Departmental Bulletin PaperTextversionpublisherKyoto UniversityArch Jpn Chir 59(3), 217～223, Mai, 1990 Effect of Glucagon on Bile Acid Metabolism after Resection of Liver Cancer in Patients with Cirrhosis TAKAAKI Suoo, HrnEAKI BEssHo，恥1ASAAKI恥1IYAMOTO,HIDETAKA KANAZAWA, CHIKAO YASUDA, TAKAHISA UCHIDA, MASAO KAWAMURA TAKASHI SHIMOTO and TAKESHI KuvAMA Second Department of Surgery, Kinki University School of Medicine, Osaka Sayama, Japan Received for Publication, Jan. 29, 1990 Abstract After hepatectomy patients with cirrhosis and liver cancer may develop progressive hepatic dysfunction and eventually hepatic failure. Insulin and glucagon are often used to treat certain kinds of hepatic dysfunction and hepatic insufficiency. We investigated the effect of glucagon on bile acid metabolism and pancreatic endocrine function. In 7 patients with severe cirrhosis and cancer of the liver, 1 mg of glucagon wぉ i町民tedintravenously pre-and post-operatively, and total bile acids, C-AMP, and bile acid fractions were determined. In the pre-operative glucagon tolerance test, the C-AMP level rose from a baseline of 14±0.8 PMol/ml to 362 ±94 PMol/ml 30 min after the injection of glucagon (p<0.01); and the level of total bile acids decreased from a baseline of 28 ± 9 μMoνml to 11±3 μMol/ml 60 min after the injection of glucagon. The post-operative C-A恥1Plevel increased from a baseline of 13 ± 1 P恥fol/mlto 192 ± 58 PMol/ml level of 30 min after the i吋ectionof glucagon (pくO01), and the post-operative level of total bile acids decreased from a baseline of 64 ± 20 μMoνml to 26±7 μMol/ml 60 min after the injection of glucagon. There was a significant correlation between the 5-min increment ratio of C-AMP and the decrement ratio of total bile acids (p<0.01). Analysis of bile acids showed that the pre-operative GCDCA level decreased from a baseline of 5,846 ± 2,853 ng/ml to 1,205 ± 436 ng/ml (pく0.05),and the pre-operative TCDCA level from 3,169± 1,384 ng/ml to 1,576±866 ng/ml 60 min after the injection of glucagon. The post-operative levels of GCDCA and TCDCA decreased from 18,487±4,257 and 7,142±2,237 ng/ml to 4,652±1,544 and 2,061±811 ng/ml, respectively; 60 min after the injection of glucagon (p <0.05). These results reveal the important role of glucagon in serum bile acid metabolism. Introduction It is well known that insulin and glucagon are essential hormones in the metabolism of glucose, Key words: Bile acid, Hepatectomy, Glucagon, Liver cirrhosis, C-AMP. 索引語：胆汁酸，肝切除， グノレコガン，肝硬変，サイクリック AMP.Present address: Second Department of Surgery, Kinki University School of Medicine, 377-2, Ohno-Higashi Osaka-Sayama, Osaka 589, Japan. 第3号（平成2年5月）protein, amino acids, lipids, electrolytes and bile acids, and in the regeneration of the liver. Insulin and glucagon are often used to treat hepatic insu伍ciency3・6・12),but little is known about the role of glucagon in bile acid metabolism a丘erhepatectomy in patients with severe cirrhosis and cancer of the liver. In this study, we investigated the effect of glucagon administration on bile acid metabolism and pancreatic endocrine function before and after hepatectomy in patients with liver cancer associated with advanced cirrhosis. 第59巻日外宝218 Table 1 GOT ????118 60 274 118 79 73 93 Alb 2.3 3.5 3.3 2.8 3.1 3.3 3.4 0-GTT linear hnear parabolic parabolic linear linear linear Ch-E 64 66 117 44 41 51 118 T. Bil 0.9 0.7 1.5 2.6 2.9 1.2 0.8 HPT （%） ? ． ，????????『 ， ，???????????「?Rm ax 0.341 0.300 0.330 0.301 0.54 0.42 0.64 R1s （%） ，????? ，?????『 ， ，?? ???????Patient No <>-----<> pre・ope－－ー一一－－＜・post-opeglucagon 1 mg " ~ μMol/R 90 80 70 60 <{ 50 ω ト 4030 20 10 0 60 Min 30 15 5 。断。l/mQ400 300 Cl. ~ 200 υ 100 。μU／叫40~ 30~ !: 20-I 10-l 0. 0 5 15 Changes of total bile acid and serum C-AMP after glucagon administration. 。60M1n. 30 15 5 ’ 60M1n 30 Fig. 1 EFFECT OF GLUCAGON ON BILE ACID METABOLISM AFTER HEPATECTOMY 219 民｛aterialsand Methods The subjects were 7 patients with liver cancer and advanced cirrhosis in whom resection of less than one segment was possible as determined by the results of tests such as ICG-Rmax, Hepaplastin, 0-GTT and serum albumin (Table 1). Glucagon tolerance test (Fig. 1 ).-20 訳c f 0 E Eコc.o 万一50。《① 田ト-80 。Y＝（一.061)X + ( -44.9) r＝ー .754p < 0.01 n = 14 。150 cAMP (5 min.%) 。pre-ope・post-ope。300 0 ． Fig. 2 Correlation between the 60-min value of total bile acids and the 5-min value of C-AMP beゐreand after surgery (p<0.01). ng/ml 7000 5000-I ｜ before 60min after n=7 4000 3000 2000 1000 GUDCA TUDCA UDCA GCA TCA CA GCDCA TCDCA GDCA TOCA COCA P<0.05 Fig. 3 Changes of preoperative bile acid fraction determinations after glucagon administration. 220 日外宝第59巻第3号（平成2年5月）One month before and after hepatectomy, fasting blood was drawn early in the morning, 1 mg of glucagon (Novo) was injected intravenously, and blood samples were taken at 5, 15, 30, and 60 min, for the determination of total bile acids, C-AMP, insulin and bile acid fractions. Blood sampling and method of measurement Blood samples were placed immediately in wells cooled below -4°C. Serum was separated in a freezing centrifuge below -4°C and stored at -20°C. Total bile acid concentrations were deter-ng/ml before 60min after n=7 8000 6000 4000 2000 Fig. 4 Changes of postoperative bile acid fraction dete口ninationsafter glucagon administration. ng/ml ~ I 18000 10000 r pre-ope post－叫児8000 6000 4000 2000 Fig. 5 Comparison of bile acid fraction deteロninationafter glucagon administration. EFFECT OF GLUCAGON ON BILE ACID METABOLISM AFTER HEPATECTOMY 221 mined with an Enzabile kit10l, C-AMP with a RIA kit (Yamasa)8l. Bile acid fractions were measured with HPLC in a column (3α－hydroxysteroid dehydrogenase immobilized on aminopropyl CPG-glass) by the method of Okuyama et al.13l The results were expressed as means± SE恥i Student’s t est was used for statistical analysis. Results 1. Glucagon tolerance test (Fig. 1) The preoperative fasting level of total bile acids in the blood was 28 ± 9 μMot/ml, and it decreas-ed gradually after the intravenous injection of 1 mg of glucagon: 26±9, 20±7, 13土4,and 11 ±3 μMol/ml at 5, 15, 30, and 60 min, respectively. On the contrary, the serum C-AMP level, which was 14±1 PMol/ml, fasting, before surgery, rose to 45±5, 289±63, 362±94, and 211±36 pMol/ml, 5, 15, 30, and 60 min, respectively, after the injection of glucagon (p<0.01). The preoperative level of fasting blood insulin was 11±1 μU/ml, and the level increased to 20±2, 26±4, 29±6, and 26土6μU/ml 5, 15, 30, and 60 min, respectively, after the injection of glucagon (p<0.05). The postoperative level of total bile acids in fasting blood was 66 ± 20 μMoll ml. The level decreased gradually to 60 ± 21 , 4 7土16,38±12, and 26±7 μMoνml 5, 15, 30, and 60 min, respec-tively, after the i吋ectionof glucagon. On the contrary, the serum C-AMP level, which was 13±1 pMol/ml, fasting, after surgery, increased to 34±6, 124±39, 192±58, and 113±30 pMol/ml 5, 15, 30, and 60 min, respectively, after the glucagon injection (p<0.01). The blood insulin level, which was 12土2μU/ml, fasting, after surge円， increasedto 28±9, 33±3, 34±6, 25±6 μU/ml, respective-ly, after the glucagon i吋ection.There was a negative correlation between the 60・minvalue of total bile acids and the 5-min value of C-AMP before and after surgery (p<0.01) (Fig. 2). The bile acid fraction determinations showed preoperative fasting GUDCA levels of 519± 163 ng/ml for GUDCA, 81 ±38 ng/n吐forTUDCA, 81土日 ng/mlfor UDCA, 1,008±494 ng/ml for GCA, 1,224±547 ng/ml for TCA, 190± 126 ng/ml for CA, 5,846±2,853 ng/ml for GCDCA, 3,169±1,384 ng/ml for TCDCA, 187±87 ng/ml for GDCA, 199士63ng/ml for TDCA, and 838 ± 676 ng/ml for CDCA. These values 60 min after the i吋ectionof glucagon were: GUDCA, 282±141 ng/ml; TUDCA, 23±36 ng/ml; UDCA, 120±41 ng/ml; GCA, 731 ±361 ng/ml; TCA, 673±283 ng/ml; CA, 275土144ng/ml; GCDCA, 1,205±436 ng/ml; TCDCA, 1,576土866ng/ml; GDCA, 91 ±59 ng/ml; TDCA, 101 ±48 ng/ml; and CDCA, 348土135ng/ml (Fig. 3). The postoperative fasting levels were: GUDCA, 860±408 ng/ml; TUDCA, 730±574 ng/ml; UDCA, 93±33 ng/ml; GCA, 1,124±462 ng/ml; TCA, 1,312±531 ng/ml; CA, 123±60 ng/ml; GCDCA, 18,487±4,257 ng/ml; TCDCA, 7,142±2,237 ng/ml; GDCA, 368土178ng/ml; TDCA, 244±90 ng/min; and CDCA, 83±15 ng/ml; 60 min after the glucagon 1吋ectionthey were: GUDCA, 1,071±778 ng/ml; TUDCA, 968士820ng/ml; UDCA, 66±56 ng/ml; GCA, 736±275 ng/ml; TCA, 1,009±491 ng/ml; CA, 180土129ng/ml; GCDCA, 4,652± 1,544 ng/ml; TCDCA, 2,061±811 ng/ml; GDCA, 160±52 ng/ml; TDCA, 155±102 ng/ml; and CDCA, 93土47ng/ml (Fig. 4). The postoperative fasting levels of GCDCA and TCDCA were much higher than the preoperative (p<0.05) (Fig. 5). 222 日外宝第59巻第3号（平成2年5月）Discussion Bile acids are synthesized from cholesterol in the liver, conjugated with glycine and taurine, and secreted into the bile (primary bile acids). In the intestines, bile acids undergo deconjugation and dehydroxylation by enterobacteria (secondary bile acids), and most of the bile acids are reabsorbed from the terminal ileum and returned to the liver via the portal circulation7・16l. Hepatic disorders cause increased levels of serum bile acids9・15l. Tanaka et al.17) ascribed the increase in serum bile acids to the following factors: 1) impaired uptake by hepatic cell membranes, 2) impaired pathway within hepatic cells through which bile acids are transported by a specific carrier protein resulting in a return of bile acids to the blood stream, 3) appearance of bile acids in the blood stream through damaged junctional complexes in bile capillaries, and 4) collateral circulation. Ohkubo et al.1) sug-gested that a factor responsible for the increase in serum bile acids in hepatic cirrhosis might be significant correlation between the portal vein index and serum bile acid levels. Bloomer et al. 1> found that serum bile acids were high in patients with severe hepatocellular injury, presumably because of impaired uptake of bile acids by hepatic cells. In their study of abnormal metabolic pathways of bile acids, V alhcevic et al.18l repo口edthat the pools of cholic acid and deoxycholic acid were reduced by a lack of 12α－hydroxylation. In the present study of patients with cirrhosis and liver cancer, the levels ofGCDCA and TCDCA were higher than normal (Fig. 3), and they increas-ed further after surgery (Fig. 5), but there were no significant changes in the other bile acid fract-ions. Dietmaier5l and Reichen et al.14) investigated the uptake of bile acids by hepatic cells using the rat hepatic perfusion system and demonstrated that bile acid uptake occurs through carrier transport and is Na+-dependent. Glucagon activates adenyl cyclase in hepatic cell membranes, and the C-AMP produced acts as a second messenger2・4). It is considered that glucagon increases Na+-depen-dent, active transport mediated by C-AMP in the hepatic cells, thus promoting bile acid upt誌がり．Glucagon also has an insulin secretion-stimulating action, and in our study insulin secretion was ac-tually increased after glucagon administration; this seems to indicate that glucagon can stimulate in sulin for ATP production, which activates hepatic cells. Conclusion When liver cancer is associated with severe cirrhosis, bile acid metabolism is disturbed and GCDCA and TCDCA are increased. After hepatectomy, this abnormality of bile acid metabolism progresses. Glucagon administration, through the elevation ofC-AMP, was found to improve post-operative bile acid metabolism. The administration of glucagon seemed, therefore, to be useful after the resection of liver cancer in patients with severe cirrhosis. References 1) Bloomer JR, Allen RM, Klatskin G: Serum bile a口idsin primarγbiliary cirhosis. Arch Intern Med 136: 57-61, 1976. 2) Broadus AE, Kaminsky NI, Noロh叩 tRC, et al: Efects of glucagon on adenosine 3’，5'-Monophosphate and glucagon 3',5'-monophosphate in human plasma and urine. J Clin Invest 49: 2237-2245, 1970. 3) Bucher NR, Swo侃eldMN: Regulation of hepatic regeneration in rats by synergistic action of insulin and glucagon. Nat Acad Sci 72: 1157-1160, 1975. 4) Corstensen HE, Bruun E, Hansen OH, et al: Glucagon stimulated plasma cyclic adenosin-3',5’ーmonophosphatein the diferential diagnosis of jaundice. Surg Gyne Obst 149：・ 503-505'1979. EFFECT OF GLUCAGON ON BILE ACID METABOLISM AFTER HEPATECTOMY 223 5) Dietmaier A, Gassel R, Graf J, et al: Investigation on the sodium dependence of bile acid flux in the isolate perfus-ed rat liver. Biochim Biophys Acta 443: 81-89, 1976. 6) Farivar M, Wands JR, lsselbacher KJ, et al: Effect of insulin and glucagon on fulminant murine hepatitis. New Engj Med 295: 1517-1519, 1976. 7) Heaton KW: Bile salts in health and disease. Churchill Livingstone Edinburgh London 1972 8) Homa M, Satoh T, Takezawa J, et al: An ultrasensitive method for the simultaneous determination of cyclic AMP and cyclic GMP in small volume samples from blood and tissue. Biochem Med: 18: 257-273, 1977. 9) Makino I, Nakagawa S, Mashima K: Conjugated and unconjugated serum bile acid levels in patients with hepatobiliary disease. Gastroenterology 56: 1033-1039, 1969. 10) Mashige F, Imai K, Osuga T: A simple and sensitive描 sayof total serum bile acids. Clin Chim Acta 70: 79-86, 1976 11) Ohkubo H, Okuda K, Iida S, et al: Role of Portal and splenic vein shunts and impaired hepatic extraction in the serum bile ac池田liver口rrhosis. Gastroenterology 86：・ 514-520,1984. 12) Okita K, Aibe T, Kaya S, et al：目 Astudy on the interaction of the therapeutic agents for hepatitis to the damaged liver cells (3). Application of glucagoninsulin therapy to the treatment of acute and chronic hepatic failure. Acta Hepato Japon 19: 854ー861,1978. 13) Okuyama S: Analysis of仕ee,glycine and taurincon chromatography and I町im。bilized3α－hydroxysteroid dehydrogenase in column fo口n.Japn J Clin Path 29: 446-458, 1981 14) Reichen J, Paumgartener G: Uptake of bile acids by perfused rat liver. Am J Physiol 231: 73←742, 1976 15) Rudman 0, Kendall FE: Bile acid content of human serum I. Serum bile acids in patients wi血hepaticdisease. J Clin Invest 36: 530-537, 1957. 16) Small DM, Dowling RH, Redinger RN: The enterohepatic circulation of bile salts. Arch Intern Med 130: 552-573, 1972. 17) Tanaka N, Ohsuga T: Serum bile acid. Japn J Clin Med 38: 689-700, 1980 18) Vachcevic ZR, Juttijudata P, Bell CC Jr, et al: Bile acid metabolism in pat問ntswith cirrhosis I, Cholic and chenodexoxycholic acid metabolism. Gastroenterology 62: 117十 1181,1972. 和文抄録硬変合併肝癌切除後における胆汁酸代謝ーとくにグルカゴンの血清胆汁酸におよぼす影響について一近畿大学医学部第2外科教室須藤峻章， ~Jj所偉光，宮本正章，金沢秀剛，保田知生内田隆久，河村正生，下戸 隆，久山 健肝硬変合併肝癌術後においては，肝機能障害の程度 汁酸，胆汁酸分画GCDCA,TCDCAが上昇しており．が進行し，肝機能不全への危険性をはらんでし、る．あ 肝切除後には，さらにこれらの胆汁酸が増加したが，る種の肝機能障害肝機能不全に対して，インスリ人 グノレカつン投与は C-AMP の上昇を介して血清胆汁グノレカ ゴン療法が行なわれているが，グルカゴン投与 酸，特に GCDCA,TCDCAを減少させる事が判明しの血清胆汁酸に及ぼす影響について検討した．高度硬 た．変合併肝癌においては胆汁酸代謝に異常を来し，総胆

硬変合併肝癌切除後における胆汁酸代謝 : とくにグルカゴンの血清胆汁酸におよぼす影響について

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硬変合併肝癌切除後における胆汁酸代謝 : とくにグルカゴンの血清胆汁酸におよぼす影響について

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