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Inhibitory effect of cimetidine on liver regeneration after two-thirds hepatectomy in rats
SCIENTIFIC PAPERS
Inhibitory Effect of Cimetidine on Liver Regeneration After Two-Thirds Hepatectomy in Rats Ryolchi Kanashima, MD, Fukuoka, Japan Naofumi Nagasue, MD, Hiroshima, Japan Motonosuke Furusawa, MD, Fukuoka, Japan Kiyoshi Inokuchi, MD, PhD, FACS, Fukuoka, Japan
Major hepatic resection has been performed with increasing frequency for treatment of various kinds of liver neoplasms and hepatic injuries [I $1. The accumulated clinical experiences have clarified that a number of complications related to liver surgery may occur. One of these complications is an acute gastroduodenal mucosal lesion, the stress ulcer syndrome, which is life threatening and has a high incidence in patients who have undergone massive hepatic resection [3,4]. In prophylaxis of this fatal complication, the therapeutic trials have been conducted mainly to reduce gastric acidity, since the prophylaxis correlates with stomach pH [5]. Cimetidine, an antagonist to histamine Hs receptors, is a potent pharmacologic inhibitor of gastric acid secretion [6]. Thus, cimetidine has been widely used with success to prevent stress-induced gastrointestinal bleeding due to a wide variety of causes [7-91. Therefore, in our institute, cimetidine is applied as a drug of first choice for the protection of patients against stress ulcer after major hepatectomy. Recently, however, several cases of hepatic disorder developing after administration of cimetidine have been reported by some practitioners with biochemical or morphologic evidence [IO-231. Furthermore, the other investigators observed a profound reduction in blood flow within the liver in healthy human subjects after introduction of this drug [14]. These findings prompted us to study whether or not cimetidine could be used safely for the residual liver with minimum functional reserve after extensive hepatic resection when it is administered for prophylaxis of postoperative, stress-induced bleeding. This study was undertaken in an attempt to invesFrom the DepMme& of Svgery, NatioMl KyushuCancer Center, F&&a. and the Hiroshima Red Cross Hospital, Hiroshima, and the Second Department of Surgery, Kyushu University School of Medicine, Fukuoka, Japan. Requests for reprints should be addressed to Ryoichl Kanashima, MD, Department of Surgery, Natlonal Kyushu Cancer Center, 595 Notame, Minamiku, Fukuoka 815. Japan.
Volume 146, September 1933
tigate the effect of cimetidine on the remaining liver after two-thirds hepatectomy in rats and to clarify the safety of this drug from the viewpoint of liver regeneration. Material and Methods Adult female albino rats (Sprague-Dawley strain) that weighed 200 to 300 g were used for investigation. Standard pilled food and water were not restricted either before or after operation. While they were under light ether anesthesia, partial hepatectomy was carried out according to the technique of Higgins and Anderson [15].Surgery was performed between 9 and 11 AM to prevent the influence of diurnal variations of the regenerative response. The whole operation took less than 10 minutes. The animal8 were divided into three groups and treated. Group I consisted of 46 rata that were subjected to twothirds hepatectomy; Group II consisted of 54 rats that received an intramuscular injection of cimetidine (40 mg/kg body weight) through the right thigh immediately and 24 and 43 hours after two-thirds hepatectomy; Group III consisted of 25 rats that had a sham operation and received 40 mgJkg body weight of cimetidine. Five to 10 rate in Groups I and II and 3 to 5 rats in Group III were killed 24,30,46, and 12 hours, and 5,7, and 14days postoperatively. Immediately before death, blood samples were taken for chemical analysis from the inferior vena cava with the rate under light ether anesthesia, and remnant livers were removed for the investigation of liver restoration, histologic characteristics, and mitotic activity. For each animal, serum albumin was measured by the method using brom cresol green. The serum activities of asparate aminotransferase and alanine aminotransferase were determined by ultraviolet spectrophotometry. For the preoperative control of these compounds, eight normal rats were exsanguinated. The regenerative rate in each experiment was obtained by dividing the moist weight of the remaining liver by the estimated preoperative weight of the whole liver and multiplying by 100. Each liver specimen was stained for histologic examinations with hematoxylin-eosin stain, and the mitotic index of hepatocytes was counted. The statis293
Kanashima et al
W lentrrative RZIte( % 1
5(
2430’48 72 Time in hours
iI i
5
7 Time in days
tical comparison for significance was performed according to the Student’s t test and the Co&ran-Cox test; a p value of less than 0.05 was considered significant.
Results No rats in Groups I and III died during the investigation (mortality rate 0 percent). To the contrary, 6 of 54 rats in Group II died during hepatectomy; 2 within 24 hours after hepatectomy, 3 between 24 and 48 hours after, and 1 between ‘72 hours and 5 days after (mortality rate 11.1 percent). Statistical differences were as follows: Group II versus I, O.O2< p <0.05; Group II versus Group III, O.l< p <0.2. The mean weight of the hepatic remnants are shown in Figure 1 as the percent of the calculated preoperative whole liver weight. The mean weight of the remaining livers increased rapidly during the first 7 days in both hepatectomized groups. In the groups treated with cimetidine (Group II) stabilization of weight gain occurred between 72 hours and 5 days postoperatively. There was no significant difference between the groups. The serum activities of alanine aminotransferase and asparate aminotransferase are serially depicted in Figure 2. The administration of cimetidine induced a significant increase in alanine aminotransferase 24 hours after hepatectomy, as compared with the alanine aminotransferase level in those who did not receive the drug. There were not substantial differences in the enzyme values thereafter during the observation between the two groups. Changes in 294
+Y
Figure 1. Wet walghta of hepatkramnanb aa the cakuiaied preqefaflve whole her w/N (moan f standad error of the mean) OF = operatkn.
peweni of
asparate aminotransferase largely followed those of alanine aminotransferase in time and sequence after hepatectomy, whereas a modest increase of this enzyme activity was observed at 72 hours in the hepatectomy and cimetidine group (Group II). In the sham operation and cimetidine group (Group III), only a slight increase in both enzyme levels was noted 24 hours postoperatively. As shown in Figure 3, Group II had a substantial decrease in the serum albumin level on the fifth postoperative day when compared with Group I. Albumin synthesis remained suppressed thereafter in Group II. The maximum mitotic activity of the hepatocytes was found 30 hours after hepatectomy in Group I, whereas it was delayed to 48 hours in the hepatectomized group receiving cimetidine (Group II) (Figure 4). Also, there was a difference in the peak values between the two groups, although it was not statistically significant (0.3< p <0.4). Few parenchymal cells were found in the phase of mitosis in Group III. Serial histologic changes in the representative livers are illustrated in Figure 5. In Group I, infiltration of fat droplets were marked during the first 48 hours. Slight dilatation of the sinusoids was seen within the fiit week. On the other hand, in Group II, profound steatosis of the hepatocytes started 48 hours postoperatively and continued until 72 hours after hepatectomy. Significant dilatation of the sinusoidal space was found between the 3rd and 14th TheAmerican
Journal of Surgery
Cimetidine and Liver Regeneration
( Karmcn Units )
S-A LT
l-b
Hepatectomy
O---_--COHepatectomy + Cimetidine A-~
F&es 2. Changeetn eemm acthfltteeufalan&re ambwtraneterese (S-AL T) andaspsrate amlnotraneteraee (S-AST) after two-thirds hepatectamy with and w/Met clmetktlne, and aiter the sham oPerath?nwith cimethillne(mean f stamiard errvr of the mean). Aeteriekslndlcate pohts~~~kaf&~-(P <&M) betweenthehePatectmnkd tFW=w = operation,
OL
L
postoperative days. In Group III, no prominent histologic abnormalities were observed.
Comments The widespread use of cimetidine, a Hz-receptor antagonist, has led to a large number of reports which claim possible or proved complications incurred by the administrationof this drug [16,17]. One of these side effects could be hepatotoxicity. Lorenzini et al [13] and others [12] independently demonstrated cimetidine-induced liver damage with electron or light microscopy. Other reports [10,11] have shown hepatic disorders on the basis of functional changes. However, the causative link between vohmm 146,aqnember 1993
’
op.
+ Cimetidine
1
“1
2430”48
Sham
72
Time in hours
i i
5
7
‘9
Time in days
liver injury and cimetidine administrationmight now be controversial, since hepatic dysfunction is rare in human subjects treated with cimetidine. Further, animal studies failed to show any hepatotoxicity of this drug [18]. As for prophylaxis of stress-induced gastrointestinal hemorrhage, cimetidine has achieved an established position in the therapeutic devices [8,9]. Macdougall et al [7] also showed in two controlled studies the significant effectiveness of cimetidine therapy compared with antacid treatment for the prevention of acute gastrointestinal bleeding in patients with fulminant hepatic failure. However, the comparison of overall survival figures among the cimetidine-treatedand nontreated groups only showed 295
Kanashimaet al
0-0
Hepatectomy
o-----o
Hepatectomy + Cimetidine Sham op. + Cimetidine
A-
*
A 2.0 -
~5.Charrgeohsenunakmmlnhwelsk,the Wee WOW (mean f standard error of the man). The astefkk tndkates stattstkal dtffer-
i I
OF!
!
‘ 2ky7’ 48 72 Time in hours
I I i
7
5
‘Y
Time in days
~(0.02
Mitotic Index
e-0
Time in hours
296
i
Hepatectomy
o-----o
Hepatectomy + Cimetidine
0-d
Sham
op.
Time in days
+ Cimetidine
F&II@ 4. Mftotkindexofhepatocyteeper 1,000 counte after two-thlrde hepatectomy wfth and without the admlnktratkn of clmetidine, and after the eham operatkn with ctmettdfne(mean f stamzta!derror of the mean). Aeterkb Indicatepotnteofetattetkaftye&t&antd~ (p
Journal ol Surgery
Cimetidine and Liver Regeneration
FlgueS.Serlaihletologkchangesdthe repreeentatlve livens ln the poops who underwent hepatectomy withoutclmetidine (a and b), and wlth clmetldlne (c and d), and the gtvup whohad tha aham opersllon wlth clmetldlne (e and f). Pa1#~a,c,andowamobtahM72ho~~ poatoperatlvely and panela b, d, and I were obtalned 14 days pqetoperatlvely. ( Hematoxylln-eoaln etaln; mapdtkatlon X 150, reduced by 30 percent. )
a trend in favor of the former, despite the control of life-threatening hemorrhage with cimetidine. Upon considering that other risk factors influencing the survival could be similar among the groups studied, it is conceivable that cimetidine itself might have deleterious effects on the treated patients. We assume that one of these effects could be associated with hepatotoxicity. In our study, the administration of a dose of cimetidine for three days after two-thirds hepatectomy induced substantial delay of liver cell proliferation. The maximum mitotic activities of the cimetidinetreated rats (Group II) were also reduced after hepatectomy as compared with those of the animals not treated with hepatectomy (Group I); however, the difference did not achieve statistical significance. Albumin synthesis in Group II remained suppressed on the fifth postoperative day and thereafter, which probably reflects impaired hepatocyte renewal. Significant elevation or reelevation of serum aminotransferase levels after hepatectomy and cimetidine administration may prove to be a harmful effect Volume 148, September 1983
of cimetidine on the regenerating liver. The continued cimetidine-induced steatosis of the remnant livers coincided well with the aforementioned biochemical and regenerative indices. Furthermore, an impressive result was the mortality in Group II, whereas there were no deaths in Groups I and III. The data obtained in this study may indicate that cimetidine, a Hz-receptor antagonist, should be administered with great care during liver regeneration after extensive hepatic resection. At least two explanations are possible for the mechanism of the inhibitory effects of cimetidine on hepatic regeneration. The first possibility is that liver cell renewal might be suppressed by cimetidine therapy due to the accompanying reduced hepatic blood flow. According to the recent study by Feely et al [14], hepatic blood flow was reduced with shortand long-term administration of cimetidine by 25 and 33 percent, respectively. Although individual flow of hepatic arterial or portal blood was not determined in their study, it is reasonable to believe that both components might be reduced, since ci297
Kanashima et al
metidine suppresses the histamine-induced increase in mesenteric, gastric, and hepatic arterial blood flow in animal studies [19-21) . Thus, impairment of liver blood flow, especially portal flow, due to hepatotrophic factors [22] which require regenerative processes could result in such inhibitory effects on hepatic cell division. Another mechanism is that of cimetidine itself, which might affect the intracellular metabolic pathways of hepatocytes during ongoing liver regeneration. Indeed, cimetidine is structurally a 4, 5-substituted imidazole, and has been found to inhibit the oxidation process in animal liver microsomes in both in vitro and in vivo studies of various drug metabolisms [23,24]. Further study concerning the direct effects of cimetidine on cell metabolism is needed, possibly using a tissue culture technique. We conclude that cimetidine has an inhibitory effect on liver regeneration and that it should be administered very carefully if applied as prophylaxis for the life-threatening stress ulcer syndrome after massive liver resection. Otherwise, antacid therapy or alternative trials should be carried out. Summary The effects of cimetidine on the regenerating liver were studied in rats after they had two-thirds hepatectomy. In Group I, standard two-thirds hepatectomy was performed. In Group II, cimetidine in a dose of 40 mg/kg was given intramuscularly immediately and 24 and 48 hours after two-thirds hepatectomy. In Group III, the same amount of cimetidine was given after a sham operation. Mortality rate, liver weight restoration, mitotic activities of remnant livers, and serum levels of aminotransferases and albumin were examined from 24 hours to 14 days after operation. The mortality rate was 11.1 percent in Group II, whereas no rats in Groups I and III died. Although there were no differences in the residual liver weights among the hepatectomized groups, treatment with cimetidine induced substantial suppression and delay of liver cell division. The serum aminotransferase levels in Group II increased significantly after hepatectomy compared with the levels in Group I. The albumin synthesis remained suppressed in Group II. Light microscopy showed prolonged liver steatosis and marked dilatation of the sinusoidal space in that group. Our results may indicate that cimetidine has an inhibitory effect on liver regeneration and that it should be administered very carefully after extensive hepatic resection if applied as prophylaxis for the life-threatening complication, stress ulcer syndrome. Otherwise, antacid therapy or other trials should be carried out. References 1. Fortner JG, Maclean BJ, Kim DK, et al. The seventies evolution in liver surgery for cancer. Cancer 1981;47:2162-6. 2. Balasegaram M, Joishy SK. Hepatic resection: the logical ap-
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3.
4.
5.
6.
7.
8.
preach to surgical management of major trauma to the liver. Am J Surg 1981;142:580-3. Foster JH, Lawler MR, Welbom MB, Holbomb GW, Sawyers JL. Recent experience with major hepatic resection. Ann Surg 1968;167:651-68. Pinkerton JA, Sawyers JL, Foster JH. A study of the postoperative course after hepatic lobectomy. Ann Surg 1971; 173:800-l 1. Hastings PR, Skillman JJ, Bushnell LS, Silen W. Antacid titration in the presentation of acute gastrointestinal bleeding. A controlled randomized trial in 100 critically ill patients, N Engl J Med 1978;298:1041-5. Brimblecombe RW, Duncan WAM, Durant 61, et al. Characterization and development of cimetidine as a histamine Hz-receptor antagonist. Gastroenterology 1978;74:33947. Macdougall BRD, Bailey RJ, Williams R. Hs-receptor antagonists and antacids in the prevention of acute gastrointestinal haemorrhage in fulminant hepatic failure: two controlled trials. Lancet 1977;1:617-9. McElwee HP, Sirinek KR, Levine BA. Cimetidine affords protection equal to antacids in prevention of stress ulceration following thermal injury. Surgery 1979:86:620-6.
9. Basso N, Bagarani M, Materia A, Fiorani S, Lunardi P, Speranza V. Cimetidine and antacid prophylaxis of acute upper gastrointestinal bleeding in high risk patients. Controlfed, randomized trial. Am J Sum 1981;141:339-41. 10. Lilly JR, Hitch DC, Javitt NB. Cimetidine cholestatic jaundice in children. J Surg Res 1978;24:384-7. 11. Villeneuve JP, Warner HA. Cimetidine hepatitis. Gastroenterology 1979;77:143-4. 12. Ruiz del Arbol L, Moreira V, Moreno A, Hertindez Ranz F, Cano A, Garcia Plaza A. Bridging hepatic necrosis associated with cimetidine. Am J Gastroenterol 1980:74:267-g. 13. Lorenzini I, Jezequel AM, Orlandi F. Cimetidine-induced hepatitis. Electron microscopic observations and clinical pattern of liver injury. Dig Dis Sci 1981;26:275-80. 14. Feely J. Wilkinson GR, Wood AJJ. Reduction of liver blood flow and propranolol metabolism by cimetidine. N Engl J Med 1981;304:692-5. 15. Higgins GM, Anderson RM. Experimental pathology of the liver. Arch Pathol 1931;12:188-202. 18. Kruss DM, Littman A. Safety of cimetidine. Gastroenterology 1978;74:478-83. 17. McGuigan JE. A consideration of the adverse effects of cimetidine. Gastroenterology 1981;80:181-92. 18. Burland WL. Evidence for the safety of cimetidine in the treatment of peptic ulcer disease. In: Creutzfeldt W, ed. Cimetidine: proceedings of an international symposium on histamine Hs-receptcr antagonists. Amsterdam-Oxford: Excerpta Medica, 1978;2:238-55. 19. Pawlik W, Tague LL, Tepperman BI, Miller TA, Jacobson ED. Histamine HI- and Hz-receptor vasodilation of canine intestinal circulation. Am J Physiol 1977;233:219-24. 20. Harvey CA, Owen DAA, Shaw KD. Evidence for both histamine HI- and H,receptors in the gastric vasculature of the cat. Br J Pharmacol 1980;69:21-7. 21. Charbon GA, Brouwers AA, Sala A. Histamine HI- and HPreceptors in the gastrointestinal circulation. Naunyn Schmiedebergs Arch Pharmacol 1980;312:123-9. 22. Starzl TE, Porter KA, Francavila JA, Benichou J, Putnam CW. A hundred years of the hepatotrophic controversy. In: Porter R, Whelan J, eds. Hepatotrophic factors. Amsterdam: Elsevier, 1978:ll l-38. 23. Wilkinson CF, Hetnarski K, Hicks LJ. Substituted imidazoles as inhibitors of microsomal oxidation and insecticide synergists. Pesticide Biochem Physiol 1974;4:299-312. 24. Soeea KV. Patwardhan RV. Avant GR. Mitchell MC, Schenker ’ S. jnhibttion of microsomal drug metabolism by histamine Hs-receptor antagonists studied in vivo and in vitro in rodents. Gastroenterology 1982;82:89-96.
The American Journal of Surgery
Inhibitory Effect of Cimetidine on Liver Regeneration After Two-Thirds Hepatectomy in Rats Ryolchi Kanashima, MD, Fukuoka, Japan Naofumi Nagasue, MD, Hiroshima, Japan Motonosuke Furusawa, MD, Fukuoka, Japan Kiyoshi Inokuchi, MD, PhD, FACS, Fukuoka, Japan
Major hepatic resection has been performed with increasing frequency for treatment of various kinds of liver neoplasms and hepatic injuries [I $1. The accumulated clinical experiences have clarified that a number of complications related to liver surgery may occur. One of these complications is an acute gastroduodenal mucosal lesion, the stress ulcer syndrome, which is life threatening and has a high incidence in patients who have undergone massive hepatic resection [3,4]. In prophylaxis of this fatal complication, the therapeutic trials have been conducted mainly to reduce gastric acidity, since the prophylaxis correlates with stomach pH [5]. Cimetidine, an antagonist to histamine Hs receptors, is a potent pharmacologic inhibitor of gastric acid secretion [6]. Thus, cimetidine has been widely used with success to prevent stress-induced gastrointestinal bleeding due to a wide variety of causes [7-91. Therefore, in our institute, cimetidine is applied as a drug of first choice for the protection of patients against stress ulcer after major hepatectomy. Recently, however, several cases of hepatic disorder developing after administration of cimetidine have been reported by some practitioners with biochemical or morphologic evidence [IO-231. Furthermore, the other investigators observed a profound reduction in blood flow within the liver in healthy human subjects after introduction of this drug [14]. These findings prompted us to study whether or not cimetidine could be used safely for the residual liver with minimum functional reserve after extensive hepatic resection when it is administered for prophylaxis of postoperative, stress-induced bleeding. This study was undertaken in an attempt to invesFrom the DepMme& of Svgery, NatioMl KyushuCancer Center, F&&a. and the Hiroshima Red Cross Hospital, Hiroshima, and the Second Department of Surgery, Kyushu University School of Medicine, Fukuoka, Japan. Requests for reprints should be addressed to Ryoichl Kanashima, MD, Department of Surgery, Natlonal Kyushu Cancer Center, 595 Notame, Minamiku, Fukuoka 815. Japan.
Volume 146, September 1933
tigate the effect of cimetidine on the remaining liver after two-thirds hepatectomy in rats and to clarify the safety of this drug from the viewpoint of liver regeneration. Material and Methods Adult female albino rats (Sprague-Dawley strain) that weighed 200 to 300 g were used for investigation. Standard pilled food and water were not restricted either before or after operation. While they were under light ether anesthesia, partial hepatectomy was carried out according to the technique of Higgins and Anderson [15].Surgery was performed between 9 and 11 AM to prevent the influence of diurnal variations of the regenerative response. The whole operation took less than 10 minutes. The animal8 were divided into three groups and treated. Group I consisted of 46 rata that were subjected to twothirds hepatectomy; Group II consisted of 54 rats that received an intramuscular injection of cimetidine (40 mg/kg body weight) through the right thigh immediately and 24 and 43 hours after two-thirds hepatectomy; Group III consisted of 25 rats that had a sham operation and received 40 mgJkg body weight of cimetidine. Five to 10 rate in Groups I and II and 3 to 5 rats in Group III were killed 24,30,46, and 12 hours, and 5,7, and 14days postoperatively. Immediately before death, blood samples were taken for chemical analysis from the inferior vena cava with the rate under light ether anesthesia, and remnant livers were removed for the investigation of liver restoration, histologic characteristics, and mitotic activity. For each animal, serum albumin was measured by the method using brom cresol green. The serum activities of asparate aminotransferase and alanine aminotransferase were determined by ultraviolet spectrophotometry. For the preoperative control of these compounds, eight normal rats were exsanguinated. The regenerative rate in each experiment was obtained by dividing the moist weight of the remaining liver by the estimated preoperative weight of the whole liver and multiplying by 100. Each liver specimen was stained for histologic examinations with hematoxylin-eosin stain, and the mitotic index of hepatocytes was counted. The statis293
Kanashima et al
W lentrrative RZIte( % 1
5(
2430’48 72 Time in hours
iI i
5
7 Time in days
tical comparison for significance was performed according to the Student’s t test and the Co&ran-Cox test; a p value of less than 0.05 was considered significant.
Results No rats in Groups I and III died during the investigation (mortality rate 0 percent). To the contrary, 6 of 54 rats in Group II died during hepatectomy; 2 within 24 hours after hepatectomy, 3 between 24 and 48 hours after, and 1 between ‘72 hours and 5 days after (mortality rate 11.1 percent). Statistical differences were as follows: Group II versus I, O.O2< p <0.05; Group II versus Group III, O.l< p <0.2. The mean weight of the hepatic remnants are shown in Figure 1 as the percent of the calculated preoperative whole liver weight. The mean weight of the remaining livers increased rapidly during the first 7 days in both hepatectomized groups. In the groups treated with cimetidine (Group II) stabilization of weight gain occurred between 72 hours and 5 days postoperatively. There was no significant difference between the groups. The serum activities of alanine aminotransferase and asparate aminotransferase are serially depicted in Figure 2. The administration of cimetidine induced a significant increase in alanine aminotransferase 24 hours after hepatectomy, as compared with the alanine aminotransferase level in those who did not receive the drug. There were not substantial differences in the enzyme values thereafter during the observation between the two groups. Changes in 294
+Y
Figure 1. Wet walghta of hepatkramnanb aa the cakuiaied preqefaflve whole her w/N (moan f standad error of the mean) OF = operatkn.
peweni of
asparate aminotransferase largely followed those of alanine aminotransferase in time and sequence after hepatectomy, whereas a modest increase of this enzyme activity was observed at 72 hours in the hepatectomy and cimetidine group (Group II). In the sham operation and cimetidine group (Group III), only a slight increase in both enzyme levels was noted 24 hours postoperatively. As shown in Figure 3, Group II had a substantial decrease in the serum albumin level on the fifth postoperative day when compared with Group I. Albumin synthesis remained suppressed thereafter in Group II. The maximum mitotic activity of the hepatocytes was found 30 hours after hepatectomy in Group I, whereas it was delayed to 48 hours in the hepatectomized group receiving cimetidine (Group II) (Figure 4). Also, there was a difference in the peak values between the two groups, although it was not statistically significant (0.3< p <0.4). Few parenchymal cells were found in the phase of mitosis in Group III. Serial histologic changes in the representative livers are illustrated in Figure 5. In Group I, infiltration of fat droplets were marked during the first 48 hours. Slight dilatation of the sinusoids was seen within the fiit week. On the other hand, in Group II, profound steatosis of the hepatocytes started 48 hours postoperatively and continued until 72 hours after hepatectomy. Significant dilatation of the sinusoidal space was found between the 3rd and 14th TheAmerican
Journal of Surgery
Cimetidine and Liver Regeneration
( Karmcn Units )
S-A LT
l-b
Hepatectomy
O---_--COHepatectomy + Cimetidine A-~
F&es 2. Changeetn eemm acthfltteeufalan&re ambwtraneterese (S-AL T) andaspsrate amlnotraneteraee (S-AST) after two-thirds hepatectamy with and w/Met clmetktlne, and aiter the sham oPerath?nwith cimethillne(mean f stamiard errvr of the mean). Aeteriekslndlcate pohts~~~kaf&~-(P <&M) betweenthehePatectmnkd tFW=w = operation,
OL
L
postoperative days. In Group III, no prominent histologic abnormalities were observed.
Comments The widespread use of cimetidine, a Hz-receptor antagonist, has led to a large number of reports which claim possible or proved complications incurred by the administrationof this drug [16,17]. One of these side effects could be hepatotoxicity. Lorenzini et al [13] and others [12] independently demonstrated cimetidine-induced liver damage with electron or light microscopy. Other reports [10,11] have shown hepatic disorders on the basis of functional changes. However, the causative link between vohmm 146,aqnember 1993
’
op.
+ Cimetidine
1
“1
2430”48
Sham
72
Time in hours
i i
5
7
‘9
Time in days
liver injury and cimetidine administrationmight now be controversial, since hepatic dysfunction is rare in human subjects treated with cimetidine. Further, animal studies failed to show any hepatotoxicity of this drug [18]. As for prophylaxis of stress-induced gastrointestinal hemorrhage, cimetidine has achieved an established position in the therapeutic devices [8,9]. Macdougall et al [7] also showed in two controlled studies the significant effectiveness of cimetidine therapy compared with antacid treatment for the prevention of acute gastrointestinal bleeding in patients with fulminant hepatic failure. However, the comparison of overall survival figures among the cimetidine-treatedand nontreated groups only showed 295
Kanashimaet al
0-0
Hepatectomy
o-----o
Hepatectomy + Cimetidine Sham op. + Cimetidine
A-
*
A 2.0 -
~5.Charrgeohsenunakmmlnhwelsk,the Wee WOW (mean f standard error of the man). The astefkk tndkates stattstkal dtffer-
i I
OF!
!
‘ 2ky7’ 48 72 Time in hours
I I i
7
5
‘Y
Time in days
~(0.02
Mitotic Index
e-0
Time in hours
296
i
Hepatectomy
o-----o
Hepatectomy + Cimetidine
0-d
Sham
op.
Time in days
+ Cimetidine
F&II@ 4. Mftotkindexofhepatocyteeper 1,000 counte after two-thlrde hepatectomy wfth and without the admlnktratkn of clmetidine, and after the eham operatkn with ctmettdfne(mean f stamzta!derror of the mean). Aeterkb Indicatepotnteofetattetkaftye&t&antd~ (p
Journal ol Surgery
Cimetidine and Liver Regeneration
FlgueS.Serlaihletologkchangesdthe repreeentatlve livens ln the poops who underwent hepatectomy withoutclmetidine (a and b), and wlth clmetldlne (c and d), and the gtvup whohad tha aham opersllon wlth clmetldlne (e and f). Pa1#~a,c,andowamobtahM72ho~~ poatoperatlvely and panela b, d, and I were obtalned 14 days pqetoperatlvely. ( Hematoxylln-eoaln etaln; mapdtkatlon X 150, reduced by 30 percent. )
a trend in favor of the former, despite the control of life-threatening hemorrhage with cimetidine. Upon considering that other risk factors influencing the survival could be similar among the groups studied, it is conceivable that cimetidine itself might have deleterious effects on the treated patients. We assume that one of these effects could be associated with hepatotoxicity. In our study, the administration of a dose of cimetidine for three days after two-thirds hepatectomy induced substantial delay of liver cell proliferation. The maximum mitotic activities of the cimetidinetreated rats (Group II) were also reduced after hepatectomy as compared with those of the animals not treated with hepatectomy (Group I); however, the difference did not achieve statistical significance. Albumin synthesis in Group II remained suppressed on the fifth postoperative day and thereafter, which probably reflects impaired hepatocyte renewal. Significant elevation or reelevation of serum aminotransferase levels after hepatectomy and cimetidine administration may prove to be a harmful effect Volume 148, September 1983
of cimetidine on the regenerating liver. The continued cimetidine-induced steatosis of the remnant livers coincided well with the aforementioned biochemical and regenerative indices. Furthermore, an impressive result was the mortality in Group II, whereas there were no deaths in Groups I and III. The data obtained in this study may indicate that cimetidine, a Hz-receptor antagonist, should be administered with great care during liver regeneration after extensive hepatic resection. At least two explanations are possible for the mechanism of the inhibitory effects of cimetidine on hepatic regeneration. The first possibility is that liver cell renewal might be suppressed by cimetidine therapy due to the accompanying reduced hepatic blood flow. According to the recent study by Feely et al [14], hepatic blood flow was reduced with shortand long-term administration of cimetidine by 25 and 33 percent, respectively. Although individual flow of hepatic arterial or portal blood was not determined in their study, it is reasonable to believe that both components might be reduced, since ci297
Kanashima et al
metidine suppresses the histamine-induced increase in mesenteric, gastric, and hepatic arterial blood flow in animal studies [19-21) . Thus, impairment of liver blood flow, especially portal flow, due to hepatotrophic factors [22] which require regenerative processes could result in such inhibitory effects on hepatic cell division. Another mechanism is that of cimetidine itself, which might affect the intracellular metabolic pathways of hepatocytes during ongoing liver regeneration. Indeed, cimetidine is structurally a 4, 5-substituted imidazole, and has been found to inhibit the oxidation process in animal liver microsomes in both in vitro and in vivo studies of various drug metabolisms [23,24]. Further study concerning the direct effects of cimetidine on cell metabolism is needed, possibly using a tissue culture technique. We conclude that cimetidine has an inhibitory effect on liver regeneration and that it should be administered very carefully if applied as prophylaxis for the life-threatening stress ulcer syndrome after massive liver resection. Otherwise, antacid therapy or alternative trials should be carried out. Summary The effects of cimetidine on the regenerating liver were studied in rats after they had two-thirds hepatectomy. In Group I, standard two-thirds hepatectomy was performed. In Group II, cimetidine in a dose of 40 mg/kg was given intramuscularly immediately and 24 and 48 hours after two-thirds hepatectomy. In Group III, the same amount of cimetidine was given after a sham operation. Mortality rate, liver weight restoration, mitotic activities of remnant livers, and serum levels of aminotransferases and albumin were examined from 24 hours to 14 days after operation. The mortality rate was 11.1 percent in Group II, whereas no rats in Groups I and III died. Although there were no differences in the residual liver weights among the hepatectomized groups, treatment with cimetidine induced substantial suppression and delay of liver cell division. The serum aminotransferase levels in Group II increased significantly after hepatectomy compared with the levels in Group I. The albumin synthesis remained suppressed in Group II. Light microscopy showed prolonged liver steatosis and marked dilatation of the sinusoidal space in that group. Our results may indicate that cimetidine has an inhibitory effect on liver regeneration and that it should be administered very carefully after extensive hepatic resection if applied as prophylaxis for the life-threatening complication, stress ulcer syndrome. Otherwise, antacid therapy or other trials should be carried out. References 1. Fortner JG, Maclean BJ, Kim DK, et al. The seventies evolution in liver surgery for cancer. Cancer 1981;47:2162-6. 2. Balasegaram M, Joishy SK. Hepatic resection: the logical ap-
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9. Basso N, Bagarani M, Materia A, Fiorani S, Lunardi P, Speranza V. Cimetidine and antacid prophylaxis of acute upper gastrointestinal bleeding in high risk patients. Controlfed, randomized trial. Am J Sum 1981;141:339-41. 10. Lilly JR, Hitch DC, Javitt NB. Cimetidine cholestatic jaundice in children. J Surg Res 1978;24:384-7. 11. Villeneuve JP, Warner HA. Cimetidine hepatitis. Gastroenterology 1979;77:143-4. 12. Ruiz del Arbol L, Moreira V, Moreno A, Hertindez Ranz F, Cano A, Garcia Plaza A. Bridging hepatic necrosis associated with cimetidine. Am J Gastroenterol 1980:74:267-g. 13. Lorenzini I, Jezequel AM, Orlandi F. Cimetidine-induced hepatitis. Electron microscopic observations and clinical pattern of liver injury. Dig Dis Sci 1981;26:275-80. 14. Feely J. Wilkinson GR, Wood AJJ. Reduction of liver blood flow and propranolol metabolism by cimetidine. N Engl J Med 1981;304:692-5. 15. Higgins GM, Anderson RM. Experimental pathology of the liver. Arch Pathol 1931;12:188-202. 18. Kruss DM, Littman A. Safety of cimetidine. Gastroenterology 1978;74:478-83. 17. McGuigan JE. A consideration of the adverse effects of cimetidine. Gastroenterology 1981;80:181-92. 18. Burland WL. Evidence for the safety of cimetidine in the treatment of peptic ulcer disease. In: Creutzfeldt W, ed. Cimetidine: proceedings of an international symposium on histamine Hs-receptcr antagonists. Amsterdam-Oxford: Excerpta Medica, 1978;2:238-55. 19. Pawlik W, Tague LL, Tepperman BI, Miller TA, Jacobson ED. Histamine HI- and Hz-receptor vasodilation of canine intestinal circulation. Am J Physiol 1977;233:219-24. 20. Harvey CA, Owen DAA, Shaw KD. Evidence for both histamine HI- and H,receptors in the gastric vasculature of the cat. Br J Pharmacol 1980;69:21-7. 21. Charbon GA, Brouwers AA, Sala A. Histamine HI- and HPreceptors in the gastrointestinal circulation. Naunyn Schmiedebergs Arch Pharmacol 1980;312:123-9. 22. Starzl TE, Porter KA, Francavila JA, Benichou J, Putnam CW. A hundred years of the hepatotrophic controversy. In: Porter R, Whelan J, eds. Hepatotrophic factors. Amsterdam: Elsevier, 1978:ll l-38. 23. Wilkinson CF, Hetnarski K, Hicks LJ. Substituted imidazoles as inhibitors of microsomal oxidation and insecticide synergists. Pesticide Biochem Physiol 1974;4:299-312. 24. Soeea KV. Patwardhan RV. Avant GR. Mitchell MC, Schenker ’ S. jnhibttion of microsomal drug metabolism by histamine Hs-receptor antagonists studied in vivo and in vitro in rodents. Gastroenterology 1982;82:89-96.
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