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Living donor liver transplant recipients achieve relatively higher immunosuppressant blood levels than cadaveric recipients
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Living Donor Liver Transplant Recipients Achieve Relatively Higher Immunosuppressant Blood Levels Than Cadaveric Recipients James F. Trotter,* Nancy Stolpman,† Michael Wachs,‡ Thomas Bak,* Marcelo Kugelmas,* Igal Kam,‡ and Gregory T. Everson* Two recent brief reports suggest that recipients of living donor liver transplants achieve higher levels of immunosuppressive agents than cadaveric (CAD) liver transplant recipients administered the same dose. These results could have important implications regarding the dosing of immunosuppressives in living donor liver transplant recipients. We report our findings relative to immunosuppressive doses and levels in a cohort of 46 living donor liver transplant recipients. Immunosuppressive blood levels and doses were recorded weeks 1, 2, 3, and 4 and months 2, 3, 4, 5, and 6 for 46 living donor liver transplant recipients and 66 matched CAD liver transplant recipients who underwent transplantation between August 1997 and May 2001. The ratio of level to dose also was recorded at each interval. The mean overall cyclosporine A dose was similar in living donor liver transplant recipients (323 mg/d) compared with CAD recipients (344 mg/d; P ⴝ not significant [NS]). The mean overall tacrolimus dose was 15% lower in patients who underwent living donor liver transplantation (LDLT; 5.7 mg/d) than CAD transplantation (6.7 mg/d), although statistical significance was not achieved (P ⴝ .08). The mean overall cyclosporine A level was 18% higher in those undergoing LDLT (275 ng/mL) than CAD transplantation (234 ng/mL; P ⴝ .015). The mean overall tacrolimus level was the same in living donor liver transplant recipients (10.8 ng/mL) and CAD recipients (10.2 ng/mL; P ⴝ NS). The overall cyclosporine A level-dose ratio was 26% higher for those undergoing LDLT (0.83) than CAD transplantation (0.66; P ⴝ .01). The overall tacrolimus level-dose ratio was 26% higher for those undergoing LDLT (1.82) than CAD transplantation (1.44; P ⴝ .01). In conclusion, (1) living donor liver transplant recipients achieve higher blood levels of tacrolimus and cyclosporine A for a given dose compared with CAD recipients, and (2) this difference is observed up to 6 months after transplantation, when hepatic regeneration is completed. (Liver Transpl 2002;8:212-218.)
From the Divisions of *Gastroenterology/Hepatology, ‡Transplant Surgery, and †Pharmacy, University of Colorado Health Sciences Center, Denver, CO. Address reprint requests to James F. Trotter, MD, 4200 E 9th Ave, B-154, Denver, CO 80262. Telephone: 303-372-8866; FAX: 303372-8868; E-mail: [email protected] Copyright © 2002 by the American Association for the Study of Liver Diseases 1527-6465/02/0803-0005$35.00/0 doi:10.1053/jlts.2002.31346
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iving donor liver transplantation (LDLT) has emerged as an effective therapy for appropriately selected patients with end-stage liver disease. The efficacy of this procedure relative to cadaveric (CAD) transplantation has been established by several centers.1-4 As experience is increasing, physicians are discovering differences between living donor liver transplant recipients and CAD transplant recipients in several areas. Recent brief reports have suggested that living donor liver transplant recipients may have more severe recurrent hepatitis C5 and less acute cellular rejection6 than CAD transplant recipients. In addition, two abstracts published this year noted greater relative blood levels of immunosuppressive drugs in living donor liver transplant recipients than CAD transplant recipients administered a similar dose. Taber et al7 reported that 13 living donor liver transplant recipients had approximately 30% higher blood levels of tacrolimus while being administered lower doses of the drug. Similar results were reported by Morgan et al8 in 16 living donor liver transplant recipients. The tacrolimus dose required to achieve the same blood level as in CAD transplant recipients was 50% lower in living donor liver transplant recipients. Based on these initial results reported in abstract form, we conducted a formal study of immunosuppressive doses and levels in our population of 46 living donor liver transplant recipients and report these findings here.
Methods All 46 adult-adult living donor liver transplant recipients who underwent LDLT at our center between August 1997 and May 2001 were included in this review. The immunosuppressive protocol used at our institution has evolved over time. Therefore, the specific immunosuppressive regimen administered varied depending on the year of transplantation. All patients were alternately assigned to either tacrolimus or cyclosporine A therapy during all intervals (administered at 8:00 AM and 8:00 PM each day). In addition to either tacrolimus or cyclosporine A, patients who underwent transplantation between August 1997 and December 1997 were administered a 14-day steroid taper with or without mycophenolate
Liver Transplantation, Vol 8, No 3 (March), 2002: pp 212-218
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mofetil. After December 1997, mycophenolate mofetil was discontinued from our immunosuppressive regimen. Patients who underwent transplantation between January 1998 and December 1999 were administered only a 14-day steroid taper in addition to either tacrolimus or cyclosporine A. Beginning January 2000, we introduced sirolimus into our immunosuppressive regimen and further reduced the duration of administration of corticosteroids to only 3 days (methylprednisolone, 1 g day 1, 500 mg day 2, 500 mg day 3). After a loading dose of 6 mg day 1, sirolimus was administered at 2 mg/d (at 12:00 noon each day), and blood levels were recorded; however, there was no adjustment of oral dose based on blood levels. CAD transplant recipients (66 patients) were matched for living donor liver transplant recipients (46 patients) based on underlying cause of liver disease and immunosuppressive regimen. Immunosuppressive doses and trough blood levels were measured in living donor liver transplant and CAD transplant recipients at the following intervals after transplantation: weeks 1, 2, 3, and 4 and months 2, 3, 4, 5, and 6. At each interval, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and serum bilirubin levels were measured. At each interval, values recorded for dose, level, and respective liver function test results represent the mean value over the preceding 7 days. We recently reported elevated levels of immunosuppressive drugs in liver transplant recipients infected with hepatitis C virus (HCV) who were administered sirolimus.9 As a result, the LDLT and CAD cohorts were balanced relative to HCV. To compare blood levels of immunosuppressive drugs for a given dose between the LDLT and CAD patient cohorts, the level-dose ratio was recorded for tacrolimus and cyclosporine A at each interval. Body weight was recorded for each patient at each interval. Data were analyzed using the Microsoft Excel Spreadsheet (Microsoft Corp, Redmond, WA). Measures of statistical significance between the two groups were made using Student’s t-test or Chi-squared analysis, when appropriate.
Results Demographics of the LDLT and CAD cohorts are listed in Table 1. There was no difference between the two groups relative to underlying liver disease, sex distribution, or administration of tacrolimus, cyclosporine A, or sirolimus. However, a significantly greater proportion of living donor liver transplant recipients underwent Roux-en-Y anastomosis (P ⬍ .05). Mean body weight for living donor liver transplant recipients was slightly lower (72.1 kg) than for CAD transplant recipients (76.9 kg; P ⫽ not significant [NS]). Doselevel ratios for tacrolimus and cyclosporine A are shown in Figures 1 and 2 and Table 2. The mean overall cyclosporine A dose was not different in living donor liver transplant recipients (323 mg/d) than CAD transplant recipients (344 mg/d; P ⫽ NS). The mean overall
Table 1. Patient Demographics LDLT No. of patients No. of men/women Men/women (%) Mean weight (kg) Hepatitis C Tacrolimus Cyclosporine A Sirolimus Biliary anastomosis Roux-en-Y Choledochocholedochostomy
CAD
46 66 28/18 45/21 57/43 68/32 72.1 76.9 23 (50) 31 (47) 31 (67) 38 (58) 15 (33) 28 (42) 26 (57) 47 (71)
P NS NS NS NS NS NS NS
32 (70) 10 (15) ⬍.05 14 (30) 56 (85) ⬍.05
NOTE. Values expressed as number (percent) unless noted otherwise.
tacrolimus dose was 15% lower in living donor liver transplant recipients than CAD transplant recipients (5.7 v 6.7 mg/d), although the difference was not statistically significant (P ⫽ .08). The overall mean cyclosporine A level for the LDLT cohort (275 ng/mL) was 18% higher than for the CAD cohort (234 ng/mL; P ⫽ .015). The overall mean tacrolimus level for the LDLT cohort (10.8 ng/mL) was not different from the CAD cohort (10.2 ng/mL; P ⫽ NS). For cyclosporine A, the overall mean level-dose ratio also was 26% higher in living donor liver transplant recipients (0.83) versus CAD transplant recipients (0.66; P ⫽ .01). For tacrolimus, the overall mean level-dose ratio was 26% higher in living donor liver transplant recipients (1.82) than CAD transplant recipients (1.44; P ⫽ .01). Table 3 lists AST, ALT, and total serum bilirubin levels in CAD and living donor transplant recipients months 1 through 6 after transplantation. AST levels were not statistically different in either group, with the exception of month 1. ALT levels were not statistically different in either group, except month 2. Bilirubin levels were not different in the LDLT compared with the CAD cohort.
Discussion Our results show that the overall mean level-dose ratio in living donor liver transplant recipients is significantly higher than in CAD transplant recipients. This finding was observed in patients administered tacrolimus, as well as cyclosporine A. Higher level-dose ratios were seen in living donor liver transplant recipients as long as 6 months after transplantation, when hepatic regeneration is believed to be complete. This indicates that
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Table 2. Mean Immunosuppressive Agent Dose, Level, and Ratio
LDLT Tacrolimus Cyclosporine A CAD Tacrolimus Cyclosporine A
Dose (mg/d)
Level (ng/mL)
Level-Dose Ratio
5.7 323
10.8 275*
1.82* 0.83*
6.7 344
10.2 234
1.44 0.66
*P ⫽ .01 in each case.
Figure 1. Cyclosporine A level-dose ratios in the CAD versus LDLT cohort. *P < .05, comparison of living donor transplant recipients with CAD transplant recipients at week 1.
living donor liver transplant recipients achieve higher trough levels of immunosuppressive drugs for a given dose than CAD transplant recipients. However, these findings do not necessarily indicate greater immunosuppressive exposure in living donor liver transplant recipients. Formal pharmacokinetic studies are required to make this determination. The mechanism(s) responsible for the higher relative levels of immunosuppressive drugs in living donor liver transplant recipients is(are) not clear. However, there are several possibilities. Blood levels of immunosuppressants in living donor liver transplant recipients may be elevated by increased absorption, decreased volume of distribution, or decreased clearance (metabolism). Increased absorption in living donor liver transplant recipients is an unlikely explanation. The only apparent difference in living donor liver transplant and CAD
Figure 2. Tacrolimus level-dose ratios in the CAD versus LDLT cohort. *P < .05, comparison of living donor liver transplant recipients with CAD transplant recipients at week 2, month 2, and month 3.
transplant recipients that could impact on absorption is the greater proportion of living donor liver transplant recipients with a Roux-en-Y anastomosis. Nearly five times as many living donor liver transplant recipients received a Roux-en-Y anastomosis compared with CAD transplant recipients. However, a Roux-en-Y anastomosis is associated with decreased immunosuppressive absorption. Because bile is introduced more distally into the intestinal tract compared with a duct-to-duct anastomosis, and cyclosporine A absorption is dependent on the presence of bile in the intestinal tract, a Roux-en-Y anastomosis may impair cyclosporine A absorption. In rats with experimentally placed blind jejunal loops, cyclosporine A absorption of reduced by 50% compared with controls.10 However, with microemulsified cyclosporine A (absorption is not bile dependent), there is no association between absorption and type of anastomosis. Tredger11 studied the absorption of microemulsified cyclosporine A in 19 patients (14 patients, duct-to-duct anastomosis; 5 patients, Rouxen-Y anastomosis) and reported no difference in cyclosporine A trough levels in the two groups of patients. Similar results were reported by Pasha et al.12 Therefore, the greater proportion of Roux-en-Y anastomoses in living donor liver transplant recipients likely has no impact on drug absorption. The volume of distribution of immunosuppressives may be smaller in living donor liver transplant recipients. (A smaller volume of distribution could increase the relative blood level of an immunosuppressant for a given dose.) The volume of distribution in living donor liver transplant recipients is likely smaller because of their relatively smaller body size (living donor liver transplant recipients are 4.8 kg or 6.2% lighter than CAD transplant recipients). However, the difference is too small to completely explain the differences in immunosuppressive level-dose ratios, which are more
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Table 3. AST, ALT, and Bilirubin Levels in the CAD and LDLT Groups AST (IU/L)
ALT (IU/L)
Bilirubin (mg/dL)
Month
CAD
LDLT
P
CAD
LDLT
P
CAD
LDLT
P
1 2 3 4 5 6
31 37 36 51 49 43
45 54 55 52 57 62
.02 .08 .07 NS NS NS
38 48 48 67 63 59
54 85 67 66 72 79
.06 .04 .10 NS NS NS
1.7 1.0 .84 .95 .98 .98
2.1 1.2 .93 .97 .97 1.3
NS NS NS NS NS NS
than 20% higher in living donor liver transplant recipients. We believe that living donor liver transplant recipients are smaller than CAD transplant recipients because of our inability to find suitable living donors for physically large patients (body weight ⬎ 100 kg). Potential living donor liver transplant recipients who weigh more than 100 kg require a donor with a similar body size. Unfortunately, most potential donors weighing more than 100 kg are obese and unlikely to be accepted as a donor. Obese donors have greater surgical risks and are likely to have significant hepatic steatosis, both of which preclude successful donation.13 Another explanation for the higher level-dose ratio in the LDLT group is reduced hepatic immunosuppressive clearance, which may be explained by two possible mechanisms. Living donor liver transplant recipients may have a smaller hepatic mass than CAD transplant recipients or reduced hepatic immunosuppressive metabolism. Recipients of right hepatic lobe living donor liver transplants receive approximately one half to two thirds as much hepatic mass as CAD transplant recipients. However, the right hepatic lobe undergoes intense proliferation immediately after transplantation. Kawasaki et al14 measured hepatic graft size implanted into four pediatric living donor liver transplant recipients and followed up hepatic regeneration with serial imaging studies. The final hepatic volume in this small number of patients “tended to approximate” standard liver volume (expected final calculated liver volume based on recipient body surface area). Tanaka et al15 published their results after following up hepatic regeneration in 28 living donor liver transplant recipients. Hepatic grafts grew to approximate calculated standard liver volume for recipients after 2 months. In the majority of patients, graft volume increased to 1.2 to 1.3 standard volumes at 3 months after LDLT and decreased to 0.8 standard volumes at 6 to 12 months. In 15 of 28 transplant recipients, the graft regenerated to less than the expected standard liver volume. In right
hepatic lobe adult living donor liver transplant recipients, Marcos et al16 reported an increase in mean hepatic graft volume from 862 to 1,202 g at 7 days and 1,458 g at 60 days after LDLT. Remarkably, living donor liver grafts reached 94% of their final regenerated volume by postoperative day 7. Calculated final liver volume based on recipient size was not performed. However, final liver volume was appropriate for the mean size of recipients (82 kg). Hepatic regeneration after small-for-size CAD liver transplantation is another model to study hepatic regeneration after transplantation. Francavilla et al17 evaluated hepatic growth and regeneration in rats weighing 200 to 250 g that received livers from 100- to 150-g donor rats. Compared with the control group (that received transplanted livers from size-matched donors), animals receiving small-for-size organs showed a rapid increase in liver volume immediately after surgery. The transplanted organ doubled in size over 14 days, reaching the same size as control animals. Hepatocyte mitosis was most rapid between days 1 and 4 posttransplantation in animals receiving small organs. Similar findings were reported in human recipients of small-for-size liver transplants. Van Thiel et al18 reported that small-for-size transplanted human livers grew at a rate of 70 mL/d until the liver reached the appropriate size for the recipient 10 to 20 days after transplantation. Factors that enhance hepatic regeneration and growth after transplantation include cyclosporine A,19 tacrolimus,20 and increased hepatic blood flow.21 Another model of hepatic regeneration is after partial hepatectomy for hepatic tumors. This situation is similar, but not identical, to LDLT. Immediately after the procedure, the patient has approximately one half of hepatic tissue, which undergoes regeneration. One of the earliest reports of hepatic regeneration after partial hepatectomy is by Higgins and Anderson.22 These investigators performed two thirds hepatectomy in rats
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and measured regeneration up to 1 month after surgery. Complete hepatic regeneration occurred in 14 days. Yamanaka et al23 published their experience in seven patients with normal livers (no hepatitis or cirrhosis) after hepatectomy of greater than 50% of liver tissue. These patients were studied by means of serial computed tomography of the abdomen. Residual liver tissue regenerated to 90% of the initial liver volume in 2 to 4 weeks. Serum albumin and bilirubin levels returned to preoperative values within 5 months after surgery. Zoli et al24 studied 12 patients who underwent partial hepatectomy. Six months after surgery, hepatic volumes were significantly less than preoperative measurements and only returned to 83% of preoperative volumes. However, hepatic function (measured by serum albumin level, prothrombin time, and cholinesterase level) returned to preoperative values by 6 months. Similar results were found by Jansen et al25 in six patients who underwent 30% to 70% partial hepatectomy. Liver volume returned to only 75% of preoperative volume. Results of studies of hepatic regeneration may be summarized as follows: after LDLT, small-forsize liver transplantation or partial hepatectomy hepatic regeneration occurs very quickly, and liver volume and function reach or approach normal after approximately 1 month or less. However, in some cases after LDLT and partial hepatectomy, the hepatic graft or liver remnant does not reach standard liver volume. Incomplete hepatic regeneration has little or no apparent clinical impact, but could explain in part the higher relative blood immunosuppressant levels in our living donor liver transplant recipients. Reduced hepatic metabolism is another possible explanation for elevated immunosuppressive levels in living donor liver transplant recipients. There is no literature evaluating drug metabolism or quantitative liver function after LDLT. However, there is a large body of data evaluating changes in quantitative hepatic metabolism after hepatectomy, which is clinically similar to implantation of a right hepatic graft. Immediately after hepatectomy, hepatic mass is reduced because of the surgical excision of hepatic tissue. As a result, the ability to clear substances through the liver is reduced. Indocyanine green half-life is increased fourfold after 60% hepatectomy and 33% after 40% hepatectomy.26 In rats after two thirds hepatectomy, the whole-organ reduced form of nicotinamide-adenine dinucleotide phosphate– cytochrome c reductase and cytochrome P-450 activity are reduced by half.27 After 90% hepatectomy, galactose clearance in rats was reduced by 90% within 24 hours after surgery.28 After partial hepatectomy, metabolic changes in the
residual hepatic tissue cause impairment in drug metabolism. Metabolic activity (in moles per gram of liver per minute) of specific enzymes responsible for drug metabolism is reduced in the remaining hepatic tissue. After two thirds hepatectomy in rats, cytochrome P-450 activity decreased from 0.92 nmol/mg/min at baseline to 0.46 nmol/mg/min at 24 hours and 0.51 nmol/mg/ min at 1 week after hepatectomy and returned to 0.82 nmol/mg/min at 2 weeks postoperatively.29 Clearance of hexobarbital (activity per gram of liver per hour) was studied in rats undergoing partial hepatectomy with and without administration of phenobarbital.30 Hexobarbital clearance (activity per gram per hour) was reduced by 50% at 36 hours after hepatectomy. However, if hepatectomy was preceded by the administration of phenobarbital (which induces enzyme activity), there was no change in hexobarbital clearance. This suggests that the reduction in enzyme activity seen after hepatectomy can be prevented by upregulation of enzyme activity by phenobarbital. Other investigators have reported similar findings relative to cytochrome P-450 activity after partial hepatectomy.31-33 At the genetic level, cytochrome P-450 gene transcription is reduced after partial hepatectomy. Changes in hepatic tissue messenger RNA (mRNA) content were measured after 90% hepatectomy in rats.34 Cytochrome P-4502B mRNA decreased 50% within 9 hours after hepatectomy. Further studies by Marie et al29 showed that mRNA degradation was accelerated and transcription of mRNA was strongly inhibited immediately after partial hepatectomy. Although cytochrome P-450 activity is reduced after hepatectomy, the activity of other enzymes is increased. Levels of mRNA for genes responsible for gluconeogenesis and the acute-phase proteins are increased up to fourfold after hepatectomy.34 Therefore, there are adaptive changes in hepatic tissue after partial hepatectomy. The activity of enzymes that support hepatic regeneration is increased, whereas activity of enzymes responsible for drug metabolism is reduced. To make a rough determination of hepatic function in CAD and living donor transplant recipients, we measured serum AST, ALT, and total bilirubin levels at each interval posttransplantation in both groups of patients. AST, ALT, and bilirubin levels were slightly greater at almost all follow-up intervals. However, there was no significant difference in bilirubin levels at any time, and statistical significance was reached only at 1 month for AST and ALT levels. Therefore, a difference in hepatic function measured by aminotransferase and bilirubin levels is unlikely to explain the difference in immunosuppressive levels between the two patient
Immunosuppressive Levels in LDLT
groups. Detection of subtle differences in hepatic function between CAD and living donor transplant recipients, if present, might require more sensitive measures of hepatic function, i.e., galactose, caffeine, and/or monoethylglycinexylidide clearance. Any decrement in hepatic function in our living donor liver transplant recipients has not been clinically evident. We have not noted clinical differences in the metabolism of other medications or noted clinical problems from reduced hepatic function in any of our living donor liver transplant recipients. In summary, we noted higher level-dose ratios for tacrolimus and cyclosporine A in our living donor liver transplant recipients compared with CAD recipients. We speculate that one or a combination of several mechanisms causes this. First, it is possible that complete hepatic regeneration to standard liver volume may not occur in all living donor liver transplant recipients. In addition, functional capacity of the regenerating LDLT graft may be reduced compared with the CAD organ. Finally, the volume of distribution in living donor liver transplant recipients may be slightly lower because of the smaller size of living donor liver transplant recipients compared with CAD transplant recipients. We currently are planning formal pharmacokinetic studies to measure the drug-metabolizing capacity and immunosuppressive exposure in living donor liver transplant recipients.
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References 1. Marcos A, Ham JM, Fisher RA, Olzinski AT, Posner MP. Single-center analysis of the first 40 adult-to-adult living donor liver transplants using the right lobe. Liver Transpl 2000;6:296-301. 2. Bak T, Wachs M, Trotter J, Everson G, Trouillot T, Kugelmas M, et al. Adult-to-adult living donor liver transplant using rightlobe grafts: Results and lessons learned from a single-center experience. Liver Transpl 2001;7:680-686. 3. Broelsch CE, Malago M, Testa G, Gamazo CV. Living donor liver transplantation in adults: Outcome in Europe. Liver Transpl 2000;6(suppl):S64-S65. 4. Todo S, Furukawa H, Jin MB, Shimamura T. Living donor liver transplantation in adults: Outcome in Japan. Liver Transpl 2000;6(suppl):S66-S72. 5. Trotter J, Schiano T, Kim-Schluger L, Bak T, Kugelmas M, Trouillot T, et al. Living donor liver transplantation in hepatitis C patients: Short-term results compared to cadaveric transplantation [abstract]. Am J Transplant 2001;1(suppl):S316A. 6. Liu LU, Schiano T, Trotter JF, Bodian C, Kim-Schluger L, Korman JD, et al. Differences in cellular rejection rates between living donor and cadaveric liver transplant recipients. Hepatology 2001;34:234A. 7. Taber DJ, Dupuis RE, Fann AL, Andreoni K, Shrestha R, Gerber D, et al. A critical analysis of tacrolimus dosing requirements
18.
19.
20.
21.
22.
23.
24.
217
and concentrations in living donor liver transplant recipients [abstract]. Am J Transplant 2001;1:369A. Morgan GR, John D, Diflo T, Teperman L. Tacrolimus dosage adjustment n adult right lobe liver transplant recipients [abstract]. Am J Transplant 2001;1:369A. Pauls T, Trotter JF, Wachs M, Bak T, Kugelmas M, Kam I, et al. Increased immunosuppressive levels in hepatitis C liver transplant recipients receiving sirolimus. Hepatology 2001; 34:245A. Whitington PF, Kehrer BH, Whitington SH, Shneider B, Black DD. The effect of biliary enteroenterostomy on the pharmacokinetics of enterally administered cyclosporine in rats. Hepatology 1989;9:393-397. Tredger JM. Using cyclosporine (Neoral) immediately after liver transplantation. United Kingdom Neoral Pilot Study Group. Ther Drug Monit 1995;17:638-641. Pasha TM, Wiesner RH, Dahlke LM, Porayko MK, Krom RA. An open-label study of the safety and tolerability of converting stable liver transplant recipients to Neoral. Liver Transpl Surg 1998;4:410-415. Rinella ME, Alonso E, Rao S, Whitington P, Fryer J, Abecassis M, et al. Body mass index as a predictor of hepatic steatosis in living liver donors. Liver Transpl 2001;7:409-414. Kawasaki S, Makuuchi M, Ishizone S, Matsunami H, Terada M, Kawarazaki H. Liver regeneration in recipients and donors after transplantation. Lancet 1992;339:580-581. Tanaka H, Harihara Y, Kita Y, Kawarasaki H, Hashizume K, Takayama T, Makuuchi M. Changes in graft volume after livingrelated liver transplantation. Transplant Proc 1999;31:28952896. Marcos A, Fisher RA, Ham JM, Shiffman ML, Sanyal AJ, Luketic VA, et al. Liver regeneration and function in donor and recipient after right lobe adult to adult living donor liver transplantation. Transplantation 2000;69:1375-1379. Francavilla A, Zeng Q, Polimeno L, Carr BI, Sun D, Porter KA, et al. Small-for-size liver transplanted into larger recipient: A model of hepatic regeneration. Hepatology 1994;19: 210-216. Van Thiel DH, Gavaler JS, Kam I, Francavilla A, Polimeno L, Schade RR, et al. Rapid growth of an intact human liver transplanted into a recipient larger than the donor. Gastroenterology 1987;93:1414-1419. Mazzaferro V, Porter K, Scotti-Foglieni CL, Venkataramanan R, Makowka L, Rossaro L, et al. The hepatotropic influence of cyclosporine. Surgery 1990;107:533-539. Starzl TE, Porter KA, Mazzaferro V, Todo S, Fung J, Francavilla A. Hepatotrophic effects of FK506 in dogs. Transplantation 1991;51:67-70. Henderson JM, Millikan WJ, Hooks M, Noe B, Kutner MH, Warren WD. Increased galactose clearance after liver transplantation: A measure of increased blood flow through the denervated liver? Hepatology 1989;10:288-291. Higgins GM, Anderson RM. Experimental pathology of the liver: Restoration of the liver of the white rat following partial surgical removal. Arch Pathol 1931;12:186-202. Yamanaka N, Okamoto E, Kawamura E, Kato T, Oriyama T, Fujimoto J, et al. Dynamics of normal and injured human liver regeneration after hepatectomy as assessed on the basis of computed tomography and liver function. Hepatology 1993;18:7985. Zoli M, Marchesini G, Melli A, Viti G, Marra A, Marrano D, et
218
25.
26.
27.
28.
29.
Trotter et al
al. Evaluation of liver volume and liver function following hepatic resection in man. Liver 1986;6:286-291. Jansen PL, Chamuleau RA, van Leeuwen DJ, Schipper HG, Busemann-Sokole E, van der Heyde MN. Liver regeneration and restoration of liver function after partial hepatectomy in patients with liver tumors. Scand J Gastroenterol 1990;25: 112-118. Prasse KW, Bjorling DE, Holmes RA, Cornelius LM. Indocyanine green clearance and ammonia tolerance in partially hepatectomized and hepatic devascularized, anesthetized dogs. Am J Vet Res 1983;44:2320-2323. Babany G, Descatoire V, Corbic M, Gendre S, Degott C, Larrey D, et al. Regulation of renal cytochrome P450: Effects of 2/3 hepatectomy, cholestasis, biliary cirrhosis and post-necrotic cirrhosis on hepatic and renal microsomal enzymes. Biochem Pharmacol 1985;34:311-320. Poulsen HE, Gaub J, Iversen J. Changes in quantitative measures of hepatic function after 90% hepatectomy in rats. Eur J Clin Invest 1985;15:285-289. Marie IJ, Dalet C, Blanchared JM, Astre C, Szawlowski A, Saint Aubert B, et al. Inhibition of cytochrome P450 (P4503A) gene
30.
31.
32.
33.
34.
expression during liver regeneration from 2/3 hepatectomy in the rat. Biochem Pharmacol 1988;37:3515-3521. Chiesara E, Clementi F, Conti F, Meldolesi J. The induction of drug-metabolizing enzymes in rat liver during growth: A biochemical and ultrastructural study. Lab Invest 1967;16: 254-267. Fouts, JR, Dixon RL, Shultice RW. The metabolism of drugs by regenerating liver. Biochem Pharmacol 1961;7:265270. Solangi K, Sacerdoti D, Goodman AI, Schwartzman ML, Abraham NG, Levere RD. Differential effects of partial hepatectomy on hepatic and renal heme and cytochrome P450 metabolism. Am J Med Sci 1988;296:387-391. Iversen PL, Liu Z, Franklin MR. Selective changes in cytochrome P-450 and UDP-glucuronosyltransferase subpopulations following partial hepatectomy in rats. Toxicol Appl Pharmacol 1985;78:10-18. Tygstrup N, Jensen SA, Krog B, Pietrangelo A, Shafritz DA. Expression of messenger RNA for liver functions following 70% and 90% hepatectomy. J Hepatol 1996;25:72-78.
Living Donor Liver Transplant Recipients Achieve Relatively Higher Immunosuppressant Blood Levels Than Cadaveric Recipients James F. Trotter,* Nancy Stolpman,† Michael Wachs,‡ Thomas Bak,* Marcelo Kugelmas,* Igal Kam,‡ and Gregory T. Everson* Two recent brief reports suggest that recipients of living donor liver transplants achieve higher levels of immunosuppressive agents than cadaveric (CAD) liver transplant recipients administered the same dose. These results could have important implications regarding the dosing of immunosuppressives in living donor liver transplant recipients. We report our findings relative to immunosuppressive doses and levels in a cohort of 46 living donor liver transplant recipients. Immunosuppressive blood levels and doses were recorded weeks 1, 2, 3, and 4 and months 2, 3, 4, 5, and 6 for 46 living donor liver transplant recipients and 66 matched CAD liver transplant recipients who underwent transplantation between August 1997 and May 2001. The ratio of level to dose also was recorded at each interval. The mean overall cyclosporine A dose was similar in living donor liver transplant recipients (323 mg/d) compared with CAD recipients (344 mg/d; P ⴝ not significant [NS]). The mean overall tacrolimus dose was 15% lower in patients who underwent living donor liver transplantation (LDLT; 5.7 mg/d) than CAD transplantation (6.7 mg/d), although statistical significance was not achieved (P ⴝ .08). The mean overall cyclosporine A level was 18% higher in those undergoing LDLT (275 ng/mL) than CAD transplantation (234 ng/mL; P ⴝ .015). The mean overall tacrolimus level was the same in living donor liver transplant recipients (10.8 ng/mL) and CAD recipients (10.2 ng/mL; P ⴝ NS). The overall cyclosporine A level-dose ratio was 26% higher for those undergoing LDLT (0.83) than CAD transplantation (0.66; P ⴝ .01). The overall tacrolimus level-dose ratio was 26% higher for those undergoing LDLT (1.82) than CAD transplantation (1.44; P ⴝ .01). In conclusion, (1) living donor liver transplant recipients achieve higher blood levels of tacrolimus and cyclosporine A for a given dose compared with CAD recipients, and (2) this difference is observed up to 6 months after transplantation, when hepatic regeneration is completed. (Liver Transpl 2002;8:212-218.)
From the Divisions of *Gastroenterology/Hepatology, ‡Transplant Surgery, and †Pharmacy, University of Colorado Health Sciences Center, Denver, CO. Address reprint requests to James F. Trotter, MD, 4200 E 9th Ave, B-154, Denver, CO 80262. Telephone: 303-372-8866; FAX: 303372-8868; E-mail: [email protected] Copyright © 2002 by the American Association for the Study of Liver Diseases 1527-6465/02/0803-0005$35.00/0 doi:10.1053/jlts.2002.31346
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iving donor liver transplantation (LDLT) has emerged as an effective therapy for appropriately selected patients with end-stage liver disease. The efficacy of this procedure relative to cadaveric (CAD) transplantation has been established by several centers.1-4 As experience is increasing, physicians are discovering differences between living donor liver transplant recipients and CAD transplant recipients in several areas. Recent brief reports have suggested that living donor liver transplant recipients may have more severe recurrent hepatitis C5 and less acute cellular rejection6 than CAD transplant recipients. In addition, two abstracts published this year noted greater relative blood levels of immunosuppressive drugs in living donor liver transplant recipients than CAD transplant recipients administered a similar dose. Taber et al7 reported that 13 living donor liver transplant recipients had approximately 30% higher blood levels of tacrolimus while being administered lower doses of the drug. Similar results were reported by Morgan et al8 in 16 living donor liver transplant recipients. The tacrolimus dose required to achieve the same blood level as in CAD transplant recipients was 50% lower in living donor liver transplant recipients. Based on these initial results reported in abstract form, we conducted a formal study of immunosuppressive doses and levels in our population of 46 living donor liver transplant recipients and report these findings here.
Methods All 46 adult-adult living donor liver transplant recipients who underwent LDLT at our center between August 1997 and May 2001 were included in this review. The immunosuppressive protocol used at our institution has evolved over time. Therefore, the specific immunosuppressive regimen administered varied depending on the year of transplantation. All patients were alternately assigned to either tacrolimus or cyclosporine A therapy during all intervals (administered at 8:00 AM and 8:00 PM each day). In addition to either tacrolimus or cyclosporine A, patients who underwent transplantation between August 1997 and December 1997 were administered a 14-day steroid taper with or without mycophenolate
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mofetil. After December 1997, mycophenolate mofetil was discontinued from our immunosuppressive regimen. Patients who underwent transplantation between January 1998 and December 1999 were administered only a 14-day steroid taper in addition to either tacrolimus or cyclosporine A. Beginning January 2000, we introduced sirolimus into our immunosuppressive regimen and further reduced the duration of administration of corticosteroids to only 3 days (methylprednisolone, 1 g day 1, 500 mg day 2, 500 mg day 3). After a loading dose of 6 mg day 1, sirolimus was administered at 2 mg/d (at 12:00 noon each day), and blood levels were recorded; however, there was no adjustment of oral dose based on blood levels. CAD transplant recipients (66 patients) were matched for living donor liver transplant recipients (46 patients) based on underlying cause of liver disease and immunosuppressive regimen. Immunosuppressive doses and trough blood levels were measured in living donor liver transplant and CAD transplant recipients at the following intervals after transplantation: weeks 1, 2, 3, and 4 and months 2, 3, 4, 5, and 6. At each interval, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and serum bilirubin levels were measured. At each interval, values recorded for dose, level, and respective liver function test results represent the mean value over the preceding 7 days. We recently reported elevated levels of immunosuppressive drugs in liver transplant recipients infected with hepatitis C virus (HCV) who were administered sirolimus.9 As a result, the LDLT and CAD cohorts were balanced relative to HCV. To compare blood levels of immunosuppressive drugs for a given dose between the LDLT and CAD patient cohorts, the level-dose ratio was recorded for tacrolimus and cyclosporine A at each interval. Body weight was recorded for each patient at each interval. Data were analyzed using the Microsoft Excel Spreadsheet (Microsoft Corp, Redmond, WA). Measures of statistical significance between the two groups were made using Student’s t-test or Chi-squared analysis, when appropriate.
Results Demographics of the LDLT and CAD cohorts are listed in Table 1. There was no difference between the two groups relative to underlying liver disease, sex distribution, or administration of tacrolimus, cyclosporine A, or sirolimus. However, a significantly greater proportion of living donor liver transplant recipients underwent Roux-en-Y anastomosis (P ⬍ .05). Mean body weight for living donor liver transplant recipients was slightly lower (72.1 kg) than for CAD transplant recipients (76.9 kg; P ⫽ not significant [NS]). Doselevel ratios for tacrolimus and cyclosporine A are shown in Figures 1 and 2 and Table 2. The mean overall cyclosporine A dose was not different in living donor liver transplant recipients (323 mg/d) than CAD transplant recipients (344 mg/d; P ⫽ NS). The mean overall
Table 1. Patient Demographics LDLT No. of patients No. of men/women Men/women (%) Mean weight (kg) Hepatitis C Tacrolimus Cyclosporine A Sirolimus Biliary anastomosis Roux-en-Y Choledochocholedochostomy
CAD
46 66 28/18 45/21 57/43 68/32 72.1 76.9 23 (50) 31 (47) 31 (67) 38 (58) 15 (33) 28 (42) 26 (57) 47 (71)
P NS NS NS NS NS NS NS
32 (70) 10 (15) ⬍.05 14 (30) 56 (85) ⬍.05
NOTE. Values expressed as number (percent) unless noted otherwise.
tacrolimus dose was 15% lower in living donor liver transplant recipients than CAD transplant recipients (5.7 v 6.7 mg/d), although the difference was not statistically significant (P ⫽ .08). The overall mean cyclosporine A level for the LDLT cohort (275 ng/mL) was 18% higher than for the CAD cohort (234 ng/mL; P ⫽ .015). The overall mean tacrolimus level for the LDLT cohort (10.8 ng/mL) was not different from the CAD cohort (10.2 ng/mL; P ⫽ NS). For cyclosporine A, the overall mean level-dose ratio also was 26% higher in living donor liver transplant recipients (0.83) versus CAD transplant recipients (0.66; P ⫽ .01). For tacrolimus, the overall mean level-dose ratio was 26% higher in living donor liver transplant recipients (1.82) than CAD transplant recipients (1.44; P ⫽ .01). Table 3 lists AST, ALT, and total serum bilirubin levels in CAD and living donor transplant recipients months 1 through 6 after transplantation. AST levels were not statistically different in either group, with the exception of month 1. ALT levels were not statistically different in either group, except month 2. Bilirubin levels were not different in the LDLT compared with the CAD cohort.
Discussion Our results show that the overall mean level-dose ratio in living donor liver transplant recipients is significantly higher than in CAD transplant recipients. This finding was observed in patients administered tacrolimus, as well as cyclosporine A. Higher level-dose ratios were seen in living donor liver transplant recipients as long as 6 months after transplantation, when hepatic regeneration is believed to be complete. This indicates that
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Table 2. Mean Immunosuppressive Agent Dose, Level, and Ratio
LDLT Tacrolimus Cyclosporine A CAD Tacrolimus Cyclosporine A
Dose (mg/d)
Level (ng/mL)
Level-Dose Ratio
5.7 323
10.8 275*
1.82* 0.83*
6.7 344
10.2 234
1.44 0.66
*P ⫽ .01 in each case.
Figure 1. Cyclosporine A level-dose ratios in the CAD versus LDLT cohort. *P < .05, comparison of living donor transplant recipients with CAD transplant recipients at week 1.
living donor liver transplant recipients achieve higher trough levels of immunosuppressive drugs for a given dose than CAD transplant recipients. However, these findings do not necessarily indicate greater immunosuppressive exposure in living donor liver transplant recipients. Formal pharmacokinetic studies are required to make this determination. The mechanism(s) responsible for the higher relative levels of immunosuppressive drugs in living donor liver transplant recipients is(are) not clear. However, there are several possibilities. Blood levels of immunosuppressants in living donor liver transplant recipients may be elevated by increased absorption, decreased volume of distribution, or decreased clearance (metabolism). Increased absorption in living donor liver transplant recipients is an unlikely explanation. The only apparent difference in living donor liver transplant and CAD
Figure 2. Tacrolimus level-dose ratios in the CAD versus LDLT cohort. *P < .05, comparison of living donor liver transplant recipients with CAD transplant recipients at week 2, month 2, and month 3.
transplant recipients that could impact on absorption is the greater proportion of living donor liver transplant recipients with a Roux-en-Y anastomosis. Nearly five times as many living donor liver transplant recipients received a Roux-en-Y anastomosis compared with CAD transplant recipients. However, a Roux-en-Y anastomosis is associated with decreased immunosuppressive absorption. Because bile is introduced more distally into the intestinal tract compared with a duct-to-duct anastomosis, and cyclosporine A absorption is dependent on the presence of bile in the intestinal tract, a Roux-en-Y anastomosis may impair cyclosporine A absorption. In rats with experimentally placed blind jejunal loops, cyclosporine A absorption of reduced by 50% compared with controls.10 However, with microemulsified cyclosporine A (absorption is not bile dependent), there is no association between absorption and type of anastomosis. Tredger11 studied the absorption of microemulsified cyclosporine A in 19 patients (14 patients, duct-to-duct anastomosis; 5 patients, Rouxen-Y anastomosis) and reported no difference in cyclosporine A trough levels in the two groups of patients. Similar results were reported by Pasha et al.12 Therefore, the greater proportion of Roux-en-Y anastomoses in living donor liver transplant recipients likely has no impact on drug absorption. The volume of distribution of immunosuppressives may be smaller in living donor liver transplant recipients. (A smaller volume of distribution could increase the relative blood level of an immunosuppressant for a given dose.) The volume of distribution in living donor liver transplant recipients is likely smaller because of their relatively smaller body size (living donor liver transplant recipients are 4.8 kg or 6.2% lighter than CAD transplant recipients). However, the difference is too small to completely explain the differences in immunosuppressive level-dose ratios, which are more
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Table 3. AST, ALT, and Bilirubin Levels in the CAD and LDLT Groups AST (IU/L)
ALT (IU/L)
Bilirubin (mg/dL)
Month
CAD
LDLT
P
CAD
LDLT
P
CAD
LDLT
P
1 2 3 4 5 6
31 37 36 51 49 43
45 54 55 52 57 62
.02 .08 .07 NS NS NS
38 48 48 67 63 59
54 85 67 66 72 79
.06 .04 .10 NS NS NS
1.7 1.0 .84 .95 .98 .98
2.1 1.2 .93 .97 .97 1.3
NS NS NS NS NS NS
than 20% higher in living donor liver transplant recipients. We believe that living donor liver transplant recipients are smaller than CAD transplant recipients because of our inability to find suitable living donors for physically large patients (body weight ⬎ 100 kg). Potential living donor liver transplant recipients who weigh more than 100 kg require a donor with a similar body size. Unfortunately, most potential donors weighing more than 100 kg are obese and unlikely to be accepted as a donor. Obese donors have greater surgical risks and are likely to have significant hepatic steatosis, both of which preclude successful donation.13 Another explanation for the higher level-dose ratio in the LDLT group is reduced hepatic immunosuppressive clearance, which may be explained by two possible mechanisms. Living donor liver transplant recipients may have a smaller hepatic mass than CAD transplant recipients or reduced hepatic immunosuppressive metabolism. Recipients of right hepatic lobe living donor liver transplants receive approximately one half to two thirds as much hepatic mass as CAD transplant recipients. However, the right hepatic lobe undergoes intense proliferation immediately after transplantation. Kawasaki et al14 measured hepatic graft size implanted into four pediatric living donor liver transplant recipients and followed up hepatic regeneration with serial imaging studies. The final hepatic volume in this small number of patients “tended to approximate” standard liver volume (expected final calculated liver volume based on recipient body surface area). Tanaka et al15 published their results after following up hepatic regeneration in 28 living donor liver transplant recipients. Hepatic grafts grew to approximate calculated standard liver volume for recipients after 2 months. In the majority of patients, graft volume increased to 1.2 to 1.3 standard volumes at 3 months after LDLT and decreased to 0.8 standard volumes at 6 to 12 months. In 15 of 28 transplant recipients, the graft regenerated to less than the expected standard liver volume. In right
hepatic lobe adult living donor liver transplant recipients, Marcos et al16 reported an increase in mean hepatic graft volume from 862 to 1,202 g at 7 days and 1,458 g at 60 days after LDLT. Remarkably, living donor liver grafts reached 94% of their final regenerated volume by postoperative day 7. Calculated final liver volume based on recipient size was not performed. However, final liver volume was appropriate for the mean size of recipients (82 kg). Hepatic regeneration after small-for-size CAD liver transplantation is another model to study hepatic regeneration after transplantation. Francavilla et al17 evaluated hepatic growth and regeneration in rats weighing 200 to 250 g that received livers from 100- to 150-g donor rats. Compared with the control group (that received transplanted livers from size-matched donors), animals receiving small-for-size organs showed a rapid increase in liver volume immediately after surgery. The transplanted organ doubled in size over 14 days, reaching the same size as control animals. Hepatocyte mitosis was most rapid between days 1 and 4 posttransplantation in animals receiving small organs. Similar findings were reported in human recipients of small-for-size liver transplants. Van Thiel et al18 reported that small-for-size transplanted human livers grew at a rate of 70 mL/d until the liver reached the appropriate size for the recipient 10 to 20 days after transplantation. Factors that enhance hepatic regeneration and growth after transplantation include cyclosporine A,19 tacrolimus,20 and increased hepatic blood flow.21 Another model of hepatic regeneration is after partial hepatectomy for hepatic tumors. This situation is similar, but not identical, to LDLT. Immediately after the procedure, the patient has approximately one half of hepatic tissue, which undergoes regeneration. One of the earliest reports of hepatic regeneration after partial hepatectomy is by Higgins and Anderson.22 These investigators performed two thirds hepatectomy in rats
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and measured regeneration up to 1 month after surgery. Complete hepatic regeneration occurred in 14 days. Yamanaka et al23 published their experience in seven patients with normal livers (no hepatitis or cirrhosis) after hepatectomy of greater than 50% of liver tissue. These patients were studied by means of serial computed tomography of the abdomen. Residual liver tissue regenerated to 90% of the initial liver volume in 2 to 4 weeks. Serum albumin and bilirubin levels returned to preoperative values within 5 months after surgery. Zoli et al24 studied 12 patients who underwent partial hepatectomy. Six months after surgery, hepatic volumes were significantly less than preoperative measurements and only returned to 83% of preoperative volumes. However, hepatic function (measured by serum albumin level, prothrombin time, and cholinesterase level) returned to preoperative values by 6 months. Similar results were found by Jansen et al25 in six patients who underwent 30% to 70% partial hepatectomy. Liver volume returned to only 75% of preoperative volume. Results of studies of hepatic regeneration may be summarized as follows: after LDLT, small-forsize liver transplantation or partial hepatectomy hepatic regeneration occurs very quickly, and liver volume and function reach or approach normal after approximately 1 month or less. However, in some cases after LDLT and partial hepatectomy, the hepatic graft or liver remnant does not reach standard liver volume. Incomplete hepatic regeneration has little or no apparent clinical impact, but could explain in part the higher relative blood immunosuppressant levels in our living donor liver transplant recipients. Reduced hepatic metabolism is another possible explanation for elevated immunosuppressive levels in living donor liver transplant recipients. There is no literature evaluating drug metabolism or quantitative liver function after LDLT. However, there is a large body of data evaluating changes in quantitative hepatic metabolism after hepatectomy, which is clinically similar to implantation of a right hepatic graft. Immediately after hepatectomy, hepatic mass is reduced because of the surgical excision of hepatic tissue. As a result, the ability to clear substances through the liver is reduced. Indocyanine green half-life is increased fourfold after 60% hepatectomy and 33% after 40% hepatectomy.26 In rats after two thirds hepatectomy, the whole-organ reduced form of nicotinamide-adenine dinucleotide phosphate– cytochrome c reductase and cytochrome P-450 activity are reduced by half.27 After 90% hepatectomy, galactose clearance in rats was reduced by 90% within 24 hours after surgery.28 After partial hepatectomy, metabolic changes in the
residual hepatic tissue cause impairment in drug metabolism. Metabolic activity (in moles per gram of liver per minute) of specific enzymes responsible for drug metabolism is reduced in the remaining hepatic tissue. After two thirds hepatectomy in rats, cytochrome P-450 activity decreased from 0.92 nmol/mg/min at baseline to 0.46 nmol/mg/min at 24 hours and 0.51 nmol/mg/ min at 1 week after hepatectomy and returned to 0.82 nmol/mg/min at 2 weeks postoperatively.29 Clearance of hexobarbital (activity per gram of liver per hour) was studied in rats undergoing partial hepatectomy with and without administration of phenobarbital.30 Hexobarbital clearance (activity per gram per hour) was reduced by 50% at 36 hours after hepatectomy. However, if hepatectomy was preceded by the administration of phenobarbital (which induces enzyme activity), there was no change in hexobarbital clearance. This suggests that the reduction in enzyme activity seen after hepatectomy can be prevented by upregulation of enzyme activity by phenobarbital. Other investigators have reported similar findings relative to cytochrome P-450 activity after partial hepatectomy.31-33 At the genetic level, cytochrome P-450 gene transcription is reduced after partial hepatectomy. Changes in hepatic tissue messenger RNA (mRNA) content were measured after 90% hepatectomy in rats.34 Cytochrome P-4502B mRNA decreased 50% within 9 hours after hepatectomy. Further studies by Marie et al29 showed that mRNA degradation was accelerated and transcription of mRNA was strongly inhibited immediately after partial hepatectomy. Although cytochrome P-450 activity is reduced after hepatectomy, the activity of other enzymes is increased. Levels of mRNA for genes responsible for gluconeogenesis and the acute-phase proteins are increased up to fourfold after hepatectomy.34 Therefore, there are adaptive changes in hepatic tissue after partial hepatectomy. The activity of enzymes that support hepatic regeneration is increased, whereas activity of enzymes responsible for drug metabolism is reduced. To make a rough determination of hepatic function in CAD and living donor transplant recipients, we measured serum AST, ALT, and total bilirubin levels at each interval posttransplantation in both groups of patients. AST, ALT, and bilirubin levels were slightly greater at almost all follow-up intervals. However, there was no significant difference in bilirubin levels at any time, and statistical significance was reached only at 1 month for AST and ALT levels. Therefore, a difference in hepatic function measured by aminotransferase and bilirubin levels is unlikely to explain the difference in immunosuppressive levels between the two patient
Immunosuppressive Levels in LDLT
groups. Detection of subtle differences in hepatic function between CAD and living donor transplant recipients, if present, might require more sensitive measures of hepatic function, i.e., galactose, caffeine, and/or monoethylglycinexylidide clearance. Any decrement in hepatic function in our living donor liver transplant recipients has not been clinically evident. We have not noted clinical differences in the metabolism of other medications or noted clinical problems from reduced hepatic function in any of our living donor liver transplant recipients. In summary, we noted higher level-dose ratios for tacrolimus and cyclosporine A in our living donor liver transplant recipients compared with CAD recipients. We speculate that one or a combination of several mechanisms causes this. First, it is possible that complete hepatic regeneration to standard liver volume may not occur in all living donor liver transplant recipients. In addition, functional capacity of the regenerating LDLT graft may be reduced compared with the CAD organ. Finally, the volume of distribution in living donor liver transplant recipients may be slightly lower because of the smaller size of living donor liver transplant recipients compared with CAD transplant recipients. We currently are planning formal pharmacokinetic studies to measure the drug-metabolizing capacity and immunosuppressive exposure in living donor liver transplant recipients.
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References 1. Marcos A, Ham JM, Fisher RA, Olzinski AT, Posner MP. Single-center analysis of the first 40 adult-to-adult living donor liver transplants using the right lobe. Liver Transpl 2000;6:296-301. 2. Bak T, Wachs M, Trotter J, Everson G, Trouillot T, Kugelmas M, et al. Adult-to-adult living donor liver transplant using rightlobe grafts: Results and lessons learned from a single-center experience. Liver Transpl 2001;7:680-686. 3. Broelsch CE, Malago M, Testa G, Gamazo CV. Living donor liver transplantation in adults: Outcome in Europe. Liver Transpl 2000;6(suppl):S64-S65. 4. Todo S, Furukawa H, Jin MB, Shimamura T. Living donor liver transplantation in adults: Outcome in Japan. Liver Transpl 2000;6(suppl):S66-S72. 5. Trotter J, Schiano T, Kim-Schluger L, Bak T, Kugelmas M, Trouillot T, et al. Living donor liver transplantation in hepatitis C patients: Short-term results compared to cadaveric transplantation [abstract]. Am J Transplant 2001;1(suppl):S316A. 6. Liu LU, Schiano T, Trotter JF, Bodian C, Kim-Schluger L, Korman JD, et al. Differences in cellular rejection rates between living donor and cadaveric liver transplant recipients. Hepatology 2001;34:234A. 7. Taber DJ, Dupuis RE, Fann AL, Andreoni K, Shrestha R, Gerber D, et al. A critical analysis of tacrolimus dosing requirements
18.
19.
20.
21.
22.
23.
24.
217
and concentrations in living donor liver transplant recipients [abstract]. Am J Transplant 2001;1:369A. Morgan GR, John D, Diflo T, Teperman L. Tacrolimus dosage adjustment n adult right lobe liver transplant recipients [abstract]. Am J Transplant 2001;1:369A. Pauls T, Trotter JF, Wachs M, Bak T, Kugelmas M, Kam I, et al. Increased immunosuppressive levels in hepatitis C liver transplant recipients receiving sirolimus. Hepatology 2001; 34:245A. Whitington PF, Kehrer BH, Whitington SH, Shneider B, Black DD. The effect of biliary enteroenterostomy on the pharmacokinetics of enterally administered cyclosporine in rats. Hepatology 1989;9:393-397. Tredger JM. Using cyclosporine (Neoral) immediately after liver transplantation. United Kingdom Neoral Pilot Study Group. Ther Drug Monit 1995;17:638-641. Pasha TM, Wiesner RH, Dahlke LM, Porayko MK, Krom RA. An open-label study of the safety and tolerability of converting stable liver transplant recipients to Neoral. Liver Transpl Surg 1998;4:410-415. Rinella ME, Alonso E, Rao S, Whitington P, Fryer J, Abecassis M, et al. Body mass index as a predictor of hepatic steatosis in living liver donors. Liver Transpl 2001;7:409-414. Kawasaki S, Makuuchi M, Ishizone S, Matsunami H, Terada M, Kawarazaki H. Liver regeneration in recipients and donors after transplantation. Lancet 1992;339:580-581. Tanaka H, Harihara Y, Kita Y, Kawarasaki H, Hashizume K, Takayama T, Makuuchi M. Changes in graft volume after livingrelated liver transplantation. Transplant Proc 1999;31:28952896. Marcos A, Fisher RA, Ham JM, Shiffman ML, Sanyal AJ, Luketic VA, et al. Liver regeneration and function in donor and recipient after right lobe adult to adult living donor liver transplantation. Transplantation 2000;69:1375-1379. Francavilla A, Zeng Q, Polimeno L, Carr BI, Sun D, Porter KA, et al. Small-for-size liver transplanted into larger recipient: A model of hepatic regeneration. Hepatology 1994;19: 210-216. Van Thiel DH, Gavaler JS, Kam I, Francavilla A, Polimeno L, Schade RR, et al. Rapid growth of an intact human liver transplanted into a recipient larger than the donor. Gastroenterology 1987;93:1414-1419. Mazzaferro V, Porter K, Scotti-Foglieni CL, Venkataramanan R, Makowka L, Rossaro L, et al. The hepatotropic influence of cyclosporine. Surgery 1990;107:533-539. Starzl TE, Porter KA, Mazzaferro V, Todo S, Fung J, Francavilla A. Hepatotrophic effects of FK506 in dogs. Transplantation 1991;51:67-70. Henderson JM, Millikan WJ, Hooks M, Noe B, Kutner MH, Warren WD. Increased galactose clearance after liver transplantation: A measure of increased blood flow through the denervated liver? Hepatology 1989;10:288-291. Higgins GM, Anderson RM. Experimental pathology of the liver: Restoration of the liver of the white rat following partial surgical removal. Arch Pathol 1931;12:186-202. Yamanaka N, Okamoto E, Kawamura E, Kato T, Oriyama T, Fujimoto J, et al. Dynamics of normal and injured human liver regeneration after hepatectomy as assessed on the basis of computed tomography and liver function. Hepatology 1993;18:7985. Zoli M, Marchesini G, Melli A, Viti G, Marra A, Marrano D, et
218
25.
26.
27.
28.
29.
Trotter et al
al. Evaluation of liver volume and liver function following hepatic resection in man. Liver 1986;6:286-291. Jansen PL, Chamuleau RA, van Leeuwen DJ, Schipper HG, Busemann-Sokole E, van der Heyde MN. Liver regeneration and restoration of liver function after partial hepatectomy in patients with liver tumors. Scand J Gastroenterol 1990;25: 112-118. Prasse KW, Bjorling DE, Holmes RA, Cornelius LM. Indocyanine green clearance and ammonia tolerance in partially hepatectomized and hepatic devascularized, anesthetized dogs. Am J Vet Res 1983;44:2320-2323. Babany G, Descatoire V, Corbic M, Gendre S, Degott C, Larrey D, et al. Regulation of renal cytochrome P450: Effects of 2/3 hepatectomy, cholestasis, biliary cirrhosis and post-necrotic cirrhosis on hepatic and renal microsomal enzymes. Biochem Pharmacol 1985;34:311-320. Poulsen HE, Gaub J, Iversen J. Changes in quantitative measures of hepatic function after 90% hepatectomy in rats. Eur J Clin Invest 1985;15:285-289. Marie IJ, Dalet C, Blanchared JM, Astre C, Szawlowski A, Saint Aubert B, et al. Inhibition of cytochrome P450 (P4503A) gene
30.
31.
32.
33.
34.
expression during liver regeneration from 2/3 hepatectomy in the rat. Biochem Pharmacol 1988;37:3515-3521. Chiesara E, Clementi F, Conti F, Meldolesi J. The induction of drug-metabolizing enzymes in rat liver during growth: A biochemical and ultrastructural study. Lab Invest 1967;16: 254-267. Fouts, JR, Dixon RL, Shultice RW. The metabolism of drugs by regenerating liver. Biochem Pharmacol 1961;7:265270. Solangi K, Sacerdoti D, Goodman AI, Schwartzman ML, Abraham NG, Levere RD. Differential effects of partial hepatectomy on hepatic and renal heme and cytochrome P450 metabolism. Am J Med Sci 1988;296:387-391. Iversen PL, Liu Z, Franklin MR. Selective changes in cytochrome P-450 and UDP-glucuronosyltransferase subpopulations following partial hepatectomy in rats. Toxicol Appl Pharmacol 1985;78:10-18. Tygstrup N, Jensen SA, Krog B, Pietrangelo A, Shafritz DA. Expression of messenger RNA for liver functions following 70% and 90% hepatectomy. J Hepatol 1996;25:72-78.