Min Tan, Feng-Feng Xu, Jun-Shen Peng, Dong-Ming Li, Liu-Hua Chen, Bao-Jun Lv, Zhen-Xian Zhao, Chen Huang, Chao-Xu Zheng, Department of General Surgery, the First Affiliated Hospital of Zhong Shan University, 58 Zhongshan 2 Road Guangzhou 510080, Guangdong Province China
Correspondence to: Dr Min Tan, Department of General Surgery, the First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan 2 Road Guangzhou 510080, Guangdong Province China. tommyt@vip.163.com
Telephone: +86-20-87766335 Fax: +86-20-87750632
Received: 2002-06-29 Accepted: 2002-07-24


Abstract
AIM: The purpose of this study was to investigate the effect of laparoscopic surgery on liver function in humans and the possible mechanisms behind such effect.

METHODS: Blood samples from 286 patients who underwent laparoscopic cholecystectomy (LC) and 40 patients who underwent open cholecystectomy (OC) were tested for liver function by measuring the level of serum alanine aminotrasferase (ALT) and aspartate aminotrasferase (AST) before and after the operations. The same tests were also applied to 18 laparoscopic colorectal cancer resection (LCR) patients and 23 open colorectal cancer resection (OCR) patients to determine whether CO₂ pneumoperitoneum could alter the serum liver enzymes.

RESULTS: The level of serum ALT and AST increased significantly during the first 48 hours post operations in both LC and LCR patients. However, no significant change of the serum liver enzymes was detected in both OC and OCR patients. As a result, there was statistically significant difference in change of both ALT and AST levels between LC and OC patients and LCR and OCR patients, respectively. By the 7th day post operation, the level of both enzymes returned to normal values in LC, OC and OCR patients except LCR patients whose enzymes remained at a higher level.

CONCLUSION: Transient elevation of hepatic transaminases occurred after laparoscopic surgery. The major causative factor seemed to be the CO₂ pneumoperitoneum. In most of the laparoscopic surgery patients, the transient elevation of serum liver enzymes showed no apparent clinical implications. However, if preoperative liver function was very poor, laparoscopic surgery may not be the best choice for the treatment of patients with certain abdominal diseases.

Tan M, Xu FF, Peng JS, Li DM, Chen LH, Lv BJ, Zhao ZX, Huang C, Zheng CX. Changes in the level of serum liver enzymes after laparoscopic surgery. World J Gastroenterol 2003; 9(2): 364-367
http://www.wjgnet.com/1007-9327/9/364.htm



INTRODUCTION
The introduction of laparoscopic surgery has profoundly changed the way for the management of patients with both gallbladder disease and common bile duct stone, and the laparoscopic cholecystectomy (LC) has become the "gold standard" in the treatment of benign gallbladder diseases such as gallbladder stone and cholecystitis^[1-4]. However, little attention has been paid to effects on liver function by laparoscopic surgery. We noticed in clinical practice that, following laparoscopic surgery, the level of certain serum liver enzymes rose markedly in most patients who had shown normal preoperative liver function tests. This clinical observation raises several questions. Are these changes of any clinical significance? What is the mechanism responsible for these changes? Do other laparoscopic operations cause the same changes? To address these questions, we conducted a prospective study to compare changes in serum liver enzymes before and after operations between LC and open cholecystectomy (OC) and laparoscopic colorectal cancer resection (LCR) with open colorectal resection (OCR).

MATERIALS AND METHODS
A total of 286 patients (102 men and 184 women with mean age of 48.6 years and range of 21-89 years) underwent elective LC from February 2001 to April 2002. During the same period, 40 patients (18 men and 22 women with mean age of 51.2 years and range of 29-86 years) with symptomatic cholelithiasis, gallbladder stone or gallbladder polypus underwent OC and were included for the study. For comparison, 18 LCR (10 men and 8 women with mean age of 62.8 years and range of 43-85 years) and 23 OCR patients (16 men and 7 women with mean age of 61.6 years and range of 39-76 years) were also selected for the study. The LCR cases included 2 descending colon cancers, 7 sigmoid colon cancers and 9 rectal cancers. The OCR patients included 4 ascending colon cancers, 6 transverse colon cancers, 1 descending colon cancers, 6 sigmoid colon cancers and 6 rectal cancers.
      All patients selected for the study had normal values of serum liver enzymes prior to the operations. The following patients were excluded from the study: those who had undergone endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic sphincterotomy (EST) within one week before laparoscopic operation. The cases who developed complications such as bile duct injury, obstruction, infection, leakage and high fever by any reason were also excluded. All colorectal cancer patients included for the study had no evidence of cancer metastasis to liver by B-ultrasonic and CT scan.
      Serum liver enzymes alanine amino transferase (ALT) and aspartate aminotransferase (AST) were measured before operations and 1, 2 and 7 days post operation to assess liver function except for LC patients. The LC patients were randomly divided into two groups before the operation, with group A of 143 LC patients tested for the liver function postoperatively on days 1 and 7 and group B of 143 patients tested for the liver function postoperatively on days 2 and 7. All LC and LCR patients received operation by one surgeon. The OC operations were performed by 3 surgeons from the same Division. The OCR operations were performed by the same team of surgical staff. All patients received general anesthesia except OC patients who received local anesthesia. The operations on LC and LCR patients were performed with four-cannula technique. During laparoscopic surgery, the intra-abdominal pressure (IAP) was maintained at a range of 12-14 mmHg. Monopolar diathermy was used in LC and OC patients to dissect the gallbladder from the liver beds. Ultrasonic scissors and bipolar diathermy were used in LCR to dissect the mesenteric vessels.
      All data were expressed as the mean ±standard deviation. Student t test was used to analyse the difference in level of serum liver enzymes before and after LC, OC, LCR and OCR. The P value less than 0.05 was considered to be statistically significant.

RESULTS
Postoperative liver failure or mortality did not occur in any of the patients studied, and all the patients were hemodynamically stable during the perioperative period.
      The level of serum ALT and AST increased significantly within 24-48 hours following operations in LC and LCR patients compared with those in OC and OCR patients (Table 1). In details, the mean pre- and post operation serum levels of ALT were respectively 23.3 U·L^-1 and 38.8 U·L^-1 in LC patients of group A (P<0.05), 21.5 U·L^-1 and 44.2U·L^-1 in LC patients of group B (P<0.01), and 22.6 U·L^-1 and 45.7 U·L^-1 in LCR patients (P<0.01). In contrast, ALT only increased from a preoperative mean of 21.8 U·L^-1 to 28.2 U·L^-1 in OC patients (P>0.05) and from 22.2 U·L^-1 to 30.6 U·L^-1 in OCR patients (P>0.05). The degree of change in ALT following the operations was greater in LC patients than that in OC patients (P<0.05, D1), P<0.01, D2), so was the change between LCR and OCR patients (P <0.05, D1 and D7), P<0.01, D2).
      Similar changes were observed in the mean value of serum AST. The AST increased significantly after operation in LC patients (from 28.4 to 41.5 U·L^-1, P<0.05, D1) and 27.1 up to 48.7 U·L^-1, P<0.01, D2) and LCR patients (from 27.3 to 40.7 U·L^-1, P<0.05, D1) and to 45.5 U·L^-1, P<0.01, D2). In OC and OCR patients, however, the AST showed only a small degree of increase (Table 1). The change of AST due to the operations was also greater in LC patients than that in OC patients (P<0.05, D1), P<0.01, D2), and so was the change between LCR and OCR (P<0.05, D1 and D7), P<0.01, D2).
      Seven days following the operations, both enzymes returned to normal value in LC, OC and OCR patients except in LCR patients whose enzymes, although lower than day 2 level, remained higher (ALT 37.2 U·L^-1, D7, P<0.05) and AST 38.6 U·L^-1 (D7, P<0.05) (Table 1).

Table 1  Preoperative and postoperative level of serum liver enzymes

n=cases, Preo-=Preoperative, ^aP<0.05, ^bP<0.01 vs Preo-; ^cP<0.05, ^dP<0.01 vs OC; ^cP<0.05, ^dP<0.01 vs OCR.

      In this study, we also tested other liver function indice such as total bilirubin (TBIL), direct bilirubin (DBIL), alkaline phosphatase (ALP), lactic dehydrogenase (LDH), total protein (TP) and gamma glutamyl transferase (GGT) (data not shown). In general, TBIL and DBIL showed a slight increase within 24-48 hours following operation in some patients, but the changes were within normal range, and these values returned to preoperative levels. Other liver function test indice did not show significant alteration.

DISCUSSION
Changes in serum levels of liver enzymes in LC rather than OC patients had been reported before^[5-9]. In order to understand whether or not CO₂ pneumoperitoneum could cause these changes, we tested the liver function of patients who received LCR or OCR. Our present studies suggest that these transient postoperative hypertransaminases in LC and LCR patients might be attributed to the following possible factors.
      The first factor of consideration was CO₂ pneumoperitoneum. Both LC and LCR patients were subject to CO₂ pneumoperitoneum during the operations and they showed significant changes in serum liver enzymes after operation. In contrast, both OC and OCR patients were under the operation conditions similar to those of LC and LCR patients except that they were not subject to CO₂ pneumoperitoneum and they showed no apparent change in the level of serum liver enzymes. This finding is consistent with other studies that showed similar changes in liver function clearance test after pneumoperitoneum^[10-16]. Because an intra-abdominal pressure (IAP) of 12-14 mmHg used in the present laparoscopic surgery was higher than the normal portal blood pressure of 7-10 mmHg, this operation might, therefore, reduce portal blood flow and cause alteration in liver function^[17-20]. On the other hand, the elevation and depression of IAP in a short time during laparoscopic operation might be causative as well. During laparoscopic procedure, the sudden alteration of IAP could cause the undulation of portal blood flow. This undulation and "re-irrigation" of organs blood flow may give rise to "ischemia and re-irrigation" damage of tissues and organs, especially the Kupffer and the endothelial cells of the hepatic sinusoids^[21]. The mesothelial cells were bulging up and the intercellular clefts thereby increased in size, and the underlying basal lamina became visible^[22]. During LC, an IAP of 8 mmHg was found to decrease the hepatic microcirculation significantly^[23,24]. Therefore, the elevation of IAP caused by CO₂ pneumoperitoneum may be the main reason behind these changes.
      A second possible mechanism for alterations of serum liver enzymes after LC is the "squeeze" pressure effect on the liver. The traction of the gallbladder may free these enzymes into the blood stream. But in our study, 40 OC were performed with a small wound within 6 cm. There should be the same or more "squeeze" pressure effect on the liver in these patients, yet the change of serum liver enzymes was different between LC and OC patients. In addition, the same changes occurred in LCR patients. This mechanism remains to be determined in animal models.
      The third possibility may be the local effect of prolonged use of diathermy to the liver surface and spread of heat to liver parenchyma. This hypothesis is supported by some other studies^[25-31]. However, similar type and intensity of diathermy were used in both OC and LC patients and it remains to be explained why the serum liver enzyme level increased in LCR patients whose focus was far from liver. While the thermal damage to liver by diathermy is generally recognized, there are no references available in the literature that compared the postoperative enzyme levels between cholecystectomies performed with and without the use of diathermy in humans.
      In addition, transient liver dysfunction occurs in patients after some general anesthesia^[32-41]. This complication is associated with anesthesia-induced changes in splanchnic blood flow and oxygen consumption. However, the anesthesia-induced hepatic hypoperfusion may not be the cause of elevation of transaminases after LC and LCR as the same anesthesia protocols was used in our 23 OCR patients who did not show marked postoperative change in serum liver enzymes. It seems that the anesthesia could not acted exclusively to cause these changes. Other studies have also shown similar liver function test results in both LC and OC cases with general anesthesia^[42].
      Another possible mechanism of alterations of serum liver enzymes that had been considered was the inadvertent clipping of the right branch of the hepatic artery or any other aberrant arterial branch supplying blood to the liver. When Calot's triangle has dense or cicatricial adhesion, the related arterial branch could be easily injured. This, however, should be followed by a massive increase in liver enzymes and usually has clinical implications^[43-45]. Nevertheless, the LCR hardly gave rise to any chance to injure the right branch of the hepatic artery, yet the LCR patients showed marked elevation of ALT and AST postoperatively. Therefore, arterial branch injury could be ruled out in almost LC patients.
      In summary, our present studies demonstrated that transient elevation of hepatic transaminases could occur after laparoscopic procedures. These changes might be attributed to hepatocellular dysfunction secondary to one or combination of CO₂ pneumoperitoneum, diathermy, extruding liver, branch of the hepatic artery injured and general anesthesia. Based on our findings, the CO₂ pneumoperitoneum might be one of the main reasons for the change of serum liver enzymes. However, the transient elevation of hepatic transaminases showed no apparent clinical implication in most patients who received laparoscopic surgery according to follow-up observations and feedback from these patients. Nevertheless, these results indicate that, if the patient's preoperative liver function was very poor, laparoscopic surgery might not be the optimal choice for treating certain abdominal diseases^[46].

REFERENCES
1   Cuschieri A. Laparoscopic cholecystectomy. J R Coll Surg Edinb 1999; 44: 187-192
2   Himal HS. Minimally invasive (laparoscopic) surgery. Surg Endosc 2002; 8: 265-270
3   Suter M, Meyer A. A 10-year experience with the use of laparoscopic cholecystectomy for acute cholecystitis: is it safe?
     Surg Endosc 2001; 15: 1187-1192
4   Kiely JM, Brannigan AE, Foley E, Cheema S, O払rien W, Delaney PV. Day case laparoscopic cholecystectomy is feasible.
     Ir J Med Sci 2001; 170: 98-99
5   Giraudo G, Brachet Contul R, Caccetta M, Morino M. Gasless laparoscopy could avoid alterations in hepatic function.
     Surg Endosc 2001; 15: 741-746
6   Morino M, Giraudo G, Festa V. Alterations in hepatic function during laparoscopic surgery. An experimental clinical study.
     Surg Endos 1998; 12: 968-972
7   Sala-Blanch X, Fontanals J, Martinez-Palli G, Taura P, Delgado S, Bosch J, Lacy AM, Visa J. Effects of carbon dioxide vs helium
     pneumoperitoneum on hepatic blood flow. Surg Endosc 1998; 12: 1121-1125
8   Kotake Y, Takeda J, Matsumoto M, Tagawa M, Kikuchi H. Subclinical hepatic dysfunction in laparoscopic cholecystectomy and
     laparoscopic colectomy. Br J Anaesth 2001; 87: 774-777
9   Andrei VE, Schein M, Margolis M, Rucinski JC, Wise L. Liver enzymes are commonly elevated following laparoscopic
     cholecystectomy: is elevated intra-abdominal pressure the cause? Dig Surg 1998; 15: 256-259
10 Sato K, Kawamura T, Wakusawa R. Hepatic blood flow and function in elderly patients undergoing laparoscopic
     cholecystectomy. Anesth Analg 2000; 90: 1198-1202
11 Takagi S. Hepatic and portal vein blood flow during carbon dioxide pneumoperitoneum for laparoscopic hepatectomy.
     Surg Endosc 1998; 12: 427-431
12 Richter S, Olinger A, Hildebrandt U, Menger MD, Vollmar B. Loss of physiologic hepatic blood flow control ("epatic arterial
     buffer response") during CO₂-pneumoperitoneum in the rat. Anesth Analg 2001; 93: 872-877
13 Perner A, Bugge K, Lyng KM, Schulze S, Kristensen PA, Bendtsen A. Changes in plasma potassium concentration during
     carbon dioxide pneumoperitoneum. Br J Anaesth 1999; 82: 137-139
14 Tunon MJ, Gonzalez P, Jorquera F, Llorente A, Gonzalo-Orden M, Gonzalez-Gallego J. Liver blood flow changes during
     laparoscopic surgery in pigs. A study of hepatic indocyanine green removal. Surg Endosc 1999; 13: 668-672
15 Klopfenstein CE, Morel DR, Clergue F, Pastor CM. Effects of abdominal CO2 insufflation and changes of position on hepatic
     blood flow in anesthetized pigs. Am J Physiol 1998; 275: H900-905
16 Schafer M, Sagesser H, Reichen J, Krahenbuhl L. Alterations in hemodynamics and hepatic and splanchnic circulation during
     laparoscopy in rats. Surg Endosc 2001; 15: 1197-1201
17 Schmandra TC, Kim ZG, Gutt CN. Effect of insufflation gas and intraabdominal pressure on portal venous flow during
     pneumoperitoneum in the rat. Surg Endosc 2001; 15: 405-408
18 Glantzounis GK, Tselepis AD, Tambaki AP, Trikalinos TA, Manataki AD, Galaris DA, Tsimoyiannis EC, Kappas AM.
     Laparoscopic surgery-induced changes in oxidative stress markers in human plasma. Surg Endosc 2001; 15: 1315-1319
19 Tsugawa K, Hashizume M, Migou S, Tanoue K, Kishihara F, Kawanaka H, Sugimachi K. The effect of carbon dioxide
     pneumoperitoneum on the portal hemodynamics in a portal-hypertensive rat model. Surg Laparosc Endosc Percutan
     Tech 1999; 9: 338-347
20 Bendet N, Morozov V, Lavi R, Panski M, Halevy A, Scapa E. Does laparoscopic cholecystectomy influence peri-sinusoidal
     cell activity? Hepatogastroenterology 1999; 46: 1603-1606
21 Volz J, Koster S, Spacek Z, Paweletz N. Characteristic alterations of the peritoneum after carbon dioxide pneumoperitoneum.
     Surg Endosc 1999; 13: 611-614
22 Gutt CN, Schmandra TC. Portal venous flow during CO2 pneumoperitoneum in the rat. Surg Endosc 1999; 13: 902-905
23 Jakimowicz J, Stultiens G, Smulders F. Laparoscopic insufflation of the abdomen reduces portal venous flow.
     Surg Endosc 1998;12: 129-132
24 Dessole S, Rubattu G, Capobianco G, Caredda S, Cherchi PL. Utility of bipolar electrocautery scissors for abdominal
     hysterectomy. Am J Obstet Gynecol 2000; 183: 396-399
25 Raut V, Bhat N, Kinsella J, Toner JG, Sinnathuray AR, Stevenson M. Bipolar scissors versus cold dissection tonsillectomy:
     a prospective, randomized, multi-unit study. Laryngoscope 2001; 111: 2178-2182
26 Tulikangas PK, Smith T, Falcone T, Boparai N, Walters MD. Gross and histologic characteristics of laparoscopic injuries
     with four different energy sources. Fertil Steril 2001; 75: 806-810
27 Capelluto E, Champault G. Variations in intraperitoneal temperature during laparoscopic cholecystectomy.
     Ann Chir 2000;125: 259-262
28 Barrat C, Capelluto E, Champault G. Intraperitoneal thermal variations during laparoscopic surgery. Surg Endosc
     1999; 13: 136-138
29 Shamiyeh A, Schrenk P, Tulipan L, Vattay P, Bogner S, Wayand W. A new bipolar feedback-controlled sealing system
     for closure of the cystic duct and artery. Surg Endosc 2002; 16: 812-813
30 Yang W, Benjamin IS, Sherwood R, Alexander B. Correlation of endothelium-dependent and -independent vasodilatation
     with liver function tests during prolonged perfusion of the rat liver. J Pharmacol Toxicol Methods 1998; 40: 227-234
31 Berger M, Junemann K, Schramm H. Danger of monopolar current in laparoscopic gallbladder surgery.
     Zentralbl Chir 2001; 126: 591-595
32 Scapa E, Pinhasov I, Eshchar J. Does general anesthesia affect sinusoidal liver cells as measured by beta-N-acetyl
     hexosaminidase serum activity level? Hepatogastroenterology 1998; 45: 1813-1815
33 Shimamoto A, Tanaka E, Mizuno D, Misawa S. Age- and sex-related changes in toluene metabolism by rat hepatic
     microsomes in vitro. Res Commun Mol Pathol Pharmacol 1999; 104: 265-276
34 Zamparelli M, Eaton S, Quant PA, McEwan A, Spitz L, Pierro A. Analgesic doses of fentanyl impair oxidative metabolism of
     neonatal hepatocytes. J Pediatr Surg 1999; 34: 260-263
35 Tanaka E, Yamazaki K, Misawa S. Update: the clinical importance of acetaminophen hepatotoxicity in non-alcoholic and
     alcoholic subjects. J Clin Pharm Ther 2000; 25: 325-332
36 Obata R, Bito H, Ohmura M, Moriwaki G, Ikeuchi Y, Katoh T, Sato S. The effects of prolonged low-flow sevoflurane anesthesia
     on renal and hepatic function. Anesth Analg 2000; 91: 1262-1268
37 Ichinose K, Yanagi F, Higashi K, Kozuma S, Akasaka T. Recurrent transient increases in liver enzymes specifically after
     isoflurane anesthesia. Masui 1999; 48: 421-423
38 Nishiyama T, Yokoyama T, Hanaoka K. Liver function after sevoflurane or isoflurane anaesthesia in neurosurgical patients.
     Can J Anaesth 1998; 45: 753-756
39 McEwen MM, Gleed RD, Ludders JW, Stokol T, Del Piero F, Erb HN. Hepatic effects of halothane and isoflurane anesthesia
     in goats. J Am Vet Med Assoc 2000; 217: 1697-1700
40 Darling JR, Sharpe PC, Stiby EK, McAteer JA, Archbold GP, Milligan KR. Serum mitochondrial aspartate transaminase activity
     after isoflurane or halothane anaesthesia. Br J Anaesth 2000; 85: 195-198
41 Feierman DE. The effect of paracetamol (acetaminophen) on fentanyl metabolism in vitro. Acta Anaesthesiol Scand
     2000; 44: 560-563
42 Saber AA, Laraja RD, Nalbandian HI, Pablos-Mendez A, Hanna K. Changes in liver function tests after laparoscopic
     cholecystectomy: not so rare, not always ominous. Am Surg 2000; 66: 699-702
43 Kayaalp C, Nessar G, Kaman S, Akoglu M. Right liver necrosis: complication of laparoscopic cholecystectomy.
     Hepatogastroenterology 2001; 48: 1727-1729
44 Balsara KP, Dubash C, Shah CR. Pseudoaneurysm of the hepatic artery along with common bile duct injury following
     laparoscopic cholecystectomy. A report of two cases. Surg Endosc 1998; 12: 276-277
45 Mathisen O, Soreide O, Bergan A. Laparoscopic cholecystectomy: bile duct and vascular injuries: management and outcome.
     Scand J Gastroenterol 2002; 37: 476-481
46 Tsuboi S, Kitano S, Yoshida T, Bandoh T, Ninomiya K, Baatar D. Effects of carbon dioxide pneumoperitoneum on
     hemodynamics in cirrhotic rats. Surg Endosc 2002; 3[epub ahead of print]

Edited by Liu HX