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Information on long-term health among living liver donors is incomplete. Because changes in standard laboratory tests may reflect underlying health among donors, pre- and post- donation results were examined in the Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL).
A2ALL followed 487 living liver donors who donated at nine U.S. transplant centers between 1998 and 2009. Aminotransferase and alkaline phosphatase activities (AST, ALT, AP), bilirubin, INR, albumin, white blood cell count (WBC), hemoglobin, platelet count, ferritin, serum creatinine and BUN were measured at evaluation and post-donation: 1 week, 1 month, 3 months, 1 year and yearly thereafter. Repeated measures models were used to estimate median lab values at each time point and test for differences between values at evaluation (baseline) and post-donation time points.
Platelet counts were significantly decreased at every time point compared to baseline, and at three years were 19% lower. Approximately 10% of donors had a platelet count ≤150 (×1000/mm3) at 2–3 years post-donation. Donors with a platelet count ≤150 (×1000/mm3) at one year had had significantly lower mean platelet counts (189±32) vs. the remainder of the cohort (267±56, p<0.0001) at evaluation. Statistically significant differences from evaluation were noted for AST, AP, INR and albumin through the first year, although most measurements were in the normal range. Median values for WBC, hemoglobin, ferritin, albumin, serum creatinine, BUN, and INR were not substantially outside the normal range at any time point.
After three months, most laboratory values return to normal among right hepatic lobe liver donors, with slower return to baseline levels for AST, AP, INR and albumin. Persistently decreased platelet counts warrant further investigation.
Donor safety is paramount to the success of living donor liver transplantation (LDLT). Thus it is imperative that transplant physicians have a complete understanding of potential complications in living donors so that the risk of the procedure may be accurately described to donor candidates and steps taken to mitigate that risk. Early in the experience of the procedure, reported complication rates1,2 were relatively low, estimated at 10 – 20 %, but reports may have underestimated complications as a result of incomplete data collection and underreporting. In addition, the full spectrum and prevalence of complications may have been underappreciated due to the relatively small numbers of patients studied and their short follow-up interval. A subsequent and more comprehensive study reported a substantially higher overall complication rate of 38%, of which 2% and 0.8% were grade 3 or 4 (serious) complications, respectively.3
Routine clinical laboratory tests are performed regularly following living donor hepatectomy to determine return to health and to help detect post-donation complications. However, there is little information on either the patterns of laboratory test results or their abnormalities. One single-center study on a subset of the donors reported herein gave results of laboratory tests up to one year after surgery. 4 Among 70 living liver donors in that study, 22 were evaluated one year post-donation. Only one had abnormal liver test results, but five (23 %) had thrombocytopenia (platelet count below 150 (×1000/mm3)). Given this relative paucity of information, we undertook this study to describe the long-term changes in common laboratory tests in living liver donors enrolled in the Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL). Because A2ALL enrolled donors prior to liver donation and attempted regular follow-up afterward, it has the ability to identify changes in laboratory results and their abnormalities. The major aims of this study were: 1) to improve understanding of potential long-term donor complications, and 2) to provide donors with more information on post-LT laboratory abnormalities.
This study included information on the 487 living donors enrolled in A2ALL for the 12-year period from 1998 through 2009 at nine U.S. transplant centers. Data were recorded by each of the participating transplant centers based on a common protocol. Through October 2004 all donor laboratory results were collected retrospectively from medical records. Laboratory results collected after October 2004 were a mixture of retrospective (in the case of patient consent after the time of initial donor evaluation) and prospective data collection. The prospective protocol specified blood tests to be measured at the initial evaluation and at 1 week, 1 month, 3 months, 12 months, and yearly post-donation. Laboratory values collected included alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AP), total bilirubin, international normalized ratio (INR), albumin, platelet count, white blood cell count (WBC), ferritin, hemoglobin (HGB), serum creatinine (SCR), and blood urea nitrogen (BUN).
The range of upper (ULN) or lower (LLN) limits of normal at the nine A2ALL centers, and the value chosen for presenting percentages above or below normal are as follows: ALT (ULN 41 – 75 (IU/L); 47), AST (ULN 35 – 59 (IU/L); 47), total bilirubin (ULN 1.1 – 1.3 (mg/dl); 1.3), alkaline phosphatase (AP) (ULN 96 – 150 (IU/L); 117), platelet count (LLN 140 – 172 (×1000/mm3); 150 (×1000/mm3)), albumin (LLN 3.4 – 4.0 (g/dl); 3.4), international normalized ratio (INR) (ULN 1.1 – 1.2; 1.1).
The study was approved by the institutional review boards and privacy boards of each of the nine participating transplant centers and the University of Michigan Data Coordinating Center. Consent of past donors (for retrospective data) and donor candidates (for prospective data) was obtained starting in September 2004.
The distributions of laboratory values over time are shown as box plots with whiskers extending to the 5th and 95th percentiles. Scatter plots of week 1, month 1, or year 1 values versus baseline values are shown for selected laboratory tests. Pearson correlation coefficients were used to estimate the strength of the linear relationship between WBC and platelet counts at several time points. Differences between the number of abnormal values at baseline and at the first follow-up at least one year later, among patients with non-missing values at both time points, were examined with McNemar’s test for paired data. Exact conditional logistic regression was used to estimate the odds ratios and 95% confidence intervals for abnormal laboratory results at follow-up versus baseline. A repeated measures model, using the Mixed procedure of SAS™, was used to estimate median laboratory values over time and to test for significant changes of post-donation values from baseline. This model used a Toeplitz covariance structure for repeated measurements on the same subject over time, and remains valid in the presence of randomly missing laboratory values. For statistical testing, all lab values were log-transformed to remove skewness. All analyses were performed using SAS version 9.2 (SAS Institute, Inc, Cary, NC).
Among the 487 living donors, mean donor age was 40 years (range 20 to 65), 88% were white, and 62% were biologically related (Table 1). Of the 487 donors, 486 had baseline, pre-donation laboratory results, and 466 (94%) had laboratory results from at least one post-donation time point (235 from 4 or more time points, 123 from 3, 76 from 2, and 32 from 1 time point).
Figure 1(a–d) and Figure 2(a–c) depict the distributions of laboratory values over time from donation through year 4. The greatest changes occurred in the immediate postoperative period, as shown in the week 1 levels, and most values approached baseline levels by three months. However, statistically significant differences in median values compared to baseline were noted for up to one year for AST, alkaline phosphatase, total bilirubin, INR, and albumin. Platelet counts were significantly lower than pre-LT at each of the follow-up intervals (Figure 2c). The average reduction in platelet count from baseline to year 4 was 16%.
Figure 3(a–d) and Figure 4(a–c) show scatter plots of the laboratory values at year 1 plotted against baseline values for each patient. Points below the equivalence line indicate patients whose one year values were lower than baseline and points above the line indicate one year values that were higher than baseline. For ALT and INR, the distribution is equally displaced around the equivalence line, suggesting that there was no overall shift in values between baseline and one year. Figures 5(a–b) show the week 1 and month 1 INR values plotted against baseline values; INR increased substantially at week 1, but was nearly back to normal at month 1. The variances of the distributions of AST (p<0.0001), alkaline phosphatase (p<0.0001) and bilirubin (p=0.09) were larger at one year compared to baseline, mostly due to more outliers at one year. Albumin showed a modest shift downward, but no difference in variance between baseline and one year (p=0.39). Figures 5(c–d) show the week 1 and month 1 albumin values plotted against baseline values; albumin decreased substantially at week 1, and recovered only partially by month 1. The most striking changes occurred in the platelet count, where there was an obvious downward shift in the platelet distribution post-donation, and a significant decrease in variance (p=0.004) at one year compared to baseline (Figure 4c). Compared to baseline, 89.4% of patients had lower platelet counts at one year. Donors with a platelet count ≤150 (×1000/mm3) at one year had had a significantly lower mean platelet count at evaluation (189±32) than the remainder of the cohort (267±56, p<0.0001).
To further investigate the relationships shown in Figures 3 and and4,4, comparisons were made of abnormal laboratory values at baseline and at the first follow-up visit that occurred one year or more post donation (Table 2), testing the likelihood of becoming abnormal when previously normal versus becoming normal when previously abnormal. Significantly more abnormal values were found at one year or later for AST, albumin, and platelet count, and nearly significant results were found for alkaline phosphatase and total bilirubin (p=0.07 and 0.08, respectively)
For all seven laboratory measures, covariates tested for their ability to predict the difference between the one year and baseline value included age, sex, weight at baseline, weight change between baseline and one year, the baseline value itself, and interactions between these variables and the baseline value. Donors tended to gain weight after transplant (mean=1.0 kg, standard deviation=5.7, p=0.02). A 10-year older age was associated with higher values at one year for ALT (b=1.9 IU/L, p=0.011), AST (b=1.7 IU/L, p=0.001), and AP (b=4.5 IU/L, p=0.0003), and with lower values for albumin (b= −0.06 g/dl, p=0.006). Women had lower values at one year for bilirubin and albumin, by an average of −0.13 mg/dl (p=0.0008) and −0.11 g/dl (p=0.030), respectively. Baseline values were highly predictive of values at one year for all laboratory measures, as is obvious in Figures 3 and and44 (p<0.05 for all; p<0.0001 for most). Weight change from baseline was significantly predictive of AP (b=0.64/kg, p=0.013), and was close to significant for ALT (b=0.30/kg, p=0.082) and bilirubin (b= 0.006/kg, p=0.086). No other factors were predictive of the change in platelets from baseline to one year.
We further tested the correlation between platelet counts and WBC, which would be expected if the drop in platelet counts were related to portal hypertension. We found significant (all p<0.0001) correlations at all time points tested (through year 3), most substantially larger than the correlation seen at baseline (r=0.23): week 1 (r=0.32), month 1 (r=0.40), month 3 (r=0.22), year 1 (r=0.35), year 2 (r=0.45), year 3 (r=0.43).
Because the higher graft weight to total liver volume ratio (GW/TLV) has been associated with both larger spleen volume and lower platelet counts following donation,17 we tested the correlation between GW/TLV and the platelet count at each post-donation time point divided by the baseline count. The early post-donation correlations were significant, but not at one year or beyond (week 1, r = −0.16, p=0.011; month 1, r = −0.19, p=0.004; month 3, r = −0.21, p=0.003; year 1, r = −0.09; p=0.29; year 2, r = −0.03, p=0.83; year 3, r = −0.08, p=0.60). We also tested GW/TLV in the year 1 platelets regression model reported above, but it was not significant (p=0.853). However, in similar models for months 1 and 3, GW/TLV was a significant predictor of a reduction in platelets. For an increase of 0.10 in GW/TLV, platelets were lower on average by 12.6 (×1000/mm3) at month 1 (p=0.013) and by 7.0 (×1000/mm3) at month 3 (p=0.013). We note that left lobe donors (n=24) had lower GW/TLV (p<0.0001) and higher platelet counts at week 1 (p=0.029) than right lobe donors. Platelet counts were not significantly different at subsequent time points between left and right lobe donors.
Additional laboratory tests were analyzed, but are not reported in detail because the findings were less likely to be clinically relevant: WBC, ferritin, HGB, SCR, and BUN. Median values of these tests followed similar trends to the laboratory medians discussed above. SCR, BUN, and HGB median values all dropped significantly from baseline to week 1 and recovered gradually to baseline values by year 1 (SCR, BUN) or year 2 (HGB). WBC peaked significantly at week 1 then returned to baseline values by month 1. Ferritin did not stabilize until year 2: it peaked at week 1, then descended below the baseline value through month 3 and slowly increased to approach the baseline value by year 2.
There are two important observations from our analyses. First, except for platelet count, laboratory values approach baseline levels within 90 days after donation. Although statistically significant differences in median values compared to evaluation were noted for up to one year for AST, alkaline phosphatase, total bilirubin, INR, and albumin, these differences at one year were very small numerically and likely to be clinically irrelevant. This information should be reassuring to donors and donor candidates as well as their physicians. Second, we found a significant reduction in platelet count. The etiology of the low platelet count is unclear, although there are several possibilities. One potential cause is that some donors could have elevated portal pressure. This could be caused by inadequate regeneration of the hepatic remnant and small remnant size, relative portal or hepatic venous insufficiency, or sinusoidal hyperperfusion leading to increased portal pressure, splenomegaly, and reduced platelet count. Second, thrombopoietin, the growth factor responsible for platelet production, is produced in the liver. A small study of 10 right hepatic lobe living donors found that thrombopoietin levels peaked seven days after surgery doubling from 12 fm/ml to 24 fm/ml.5 The increase in thrombopoietin corresponded with a doubling of platelet count. If post-operative hepatic regeneration were incomplete, the reduction in hepatic mass could lead to reduced thrombopoietin levels and a reduction in platelet count. Finally, portal vein thrombosis has been reported in < 1 % of living liver donors. Complete thrombosis or partial stenosis of the portal vein could result in splenomegaly and subsequent thrombocytopenia.2,4,6,7
Numerous studies have reported changes in laboratory tests immediately after hepatic lobe donation. As noted above, all except one study4 measured values in the immediate post-operative period (< 30 days). Peak values of AST and ALT were noted on the day of or day after surgery8–14 and then returned to normal (or approached normal) between five days and one month. Maximum post-operative bilirubin values generally occurred somewhat later than AST and ALT, peaking between one and seven days followed by return to normal or near normal between seven and 30 days.8–10,12,13,15,16 INR or prothrombin time were evaluated in fewer studies and reached a peak between one and two days after surgery and returned to or approached baseline levels between seven and 14 days after surgery.8–10,12–14,16 The platelet count dropped in as many as one-half of patients and reached a nadir at approximately three days.14,5,17,10 Values returned to or approached normal levels by 30 days, but this was evaluated in only one study. Spleen size was evaluated in a few studies and increased 34 to 52 % from baseline size by seven days to six months.5,18,19 Spleen measurements were not available for our analyses, but are being undertaken.
Our analysis differed in several important respects compared to these previously published reports. The number of donors evaluated in the above-mentioned studies was relatively small with a mean and median of 88 and 52 patients, respectively. In addition, these studies evaluated changes in laboratory tests only in the immediate post-operative period, and rarely after more than 14 days. None made statistical comparisons between baseline and follow-up values. As a result, the changes in laboratory tests over time were largely descriptive and not quantitative. However, these studies reported more values during the immediate post-operative period (usually on a daily basis) than our study. Therefore, our study likely did not capture the greatest changes which typically occurred within seven days of the operation. In this regard, the most striking difference between our study and other published reports occurred with respect to platelet counts. In earlier studies, platelet count increased from baseline in the first one to three post-operative days and decreased thereafter. Because our analysis did not report values before day seven, we may have missed an immediate but transient post-operative increase in platelet count. Our study has follow-up data for a much longer period of time for a large number of donors at specified intervals long after 30 days post-donation.
There are several shortcomings of our analysis. We do not have data during the immediate (<7 day) post-operative period when the greatest changes are noted in the laboratory tests. In addition, not every donor had data at each of the follow-up intervals. This could lead to under-reporting of abnormal tests of donors with complications, or could lead to over-estimates of abnormalities if those with normal values were less likely to be tested. Also, follow-up laboratory tests were performed at multiple clinical laboratories. The baseline and the one week values were measured at the transplant center performing the donation. Thereafter, some tests were done outside the transplant center, adding some variability due to differing normal values ranges for each test among clinical laboratories. We also noted that a small percentage of donors underwent living liver donation with mild abnormalities in their baseline laboratory tests at the time of operation, most commonly ALT, bilirubin and INR. However, the number of patients with these abnormalities was insufficient to make any meaningful observations about outcomes.
In conclusion, we found that most blood tests aside from platelet count return to the normal range and approach baseline levels within one year of operation in living liver donors, although the probability of abnormal values remained elevated for AST, AP, INR and albumin. The cause of low platelet counts in living liver donors warrants further evaluation. This information may be used by donors, donor candidates and their physicians relative to the further understanding outcomes following live liver donation.
This study was supported by National Institute of Diabetes & Digestive & Kidney Diseases through cooperative agreements (listed below). Additional support was provided by Health Resources and Services Administration (HRSA), and the American Society of Transplant Surgeons (ASTS).
The following individuals were instrumental in the planning, conduct and/or care of patients enrolled in this study at each of the participating institutions as follows:
Columbia University Health Sciences, New York, NY (DK62483): PI: Jean C. Emond, MD; Co-PI: Robert S. Brown, Jr., MD, MPH; Study Coordinators: Scott Heese, BA; Jonah S. Zaretsky, BA
Northwestern University, Chicago, IL (DK62467): PI: Michael M.I. Abecassis, MD, MBA; Co-PI: Laura M. Kulik, MD; Study Coordinator: Patrice Al-Saden, RN, CCRC
University of Pennsylvania Health System, Philadelphia, PA (DK62494): PI: Abraham Shaked, MD, PhD; Co-PI: Kim M. Olthoff, MD; Study Coordinators: Brian Conboy, PA, MBA; Mary Shaw, RN, BBA
University of Colorado Health Sciences Center, Denver, CO (DK62536): PI: Gregory T. Everson, MD; Co-PI: Igal Kam, MD; Study Coordinators: Carlos Garcia, BS, Anastasia Krajec, RN
University of California Los Angeles, Los Angeles, CA (DK62496): PI: Johnny C. Hong, MD; Co-PI: Ronald W. Busuttil, MD, PhD; Study Coordinator: Janet Mooney, RN, BSN
University of California San Francisco, San Francisco, CA (DK62444): PI: Chris E. Freise, MD, FACS; Co-PI: Norah A. Terrault, MD; Study Coordinator: Dulce MacLeod, RN
University of Michigan Medical Center, Ann Arbor, MI (DK62498): PI: Robert M. Merion, MD; DCC Staff: Anna S.F. Lok, MD; Akinlolu O. Ojo, MD, PhD; Brenda W. Gillespie, PhD; Margaret Hill-Callahan, BS, LSW; Terese Howell, BS, ACRP; Lisa Holloway, BS, ACRP; Mary Akagi, MS, CCRP; Monique Lowe, BS; Abby Smith, BA; Abby Brithinee, BA
University of North Carolina, Chapel Hill, NC (DK62505): PI: Paul H. Hayashi, MD, MPH; Study Coordinator: Tracy Russell, MA
University of Virginia (DK62484): PI: Carl L. Berg, MD; Study Coordinator: Jaye Davis, RN
Medical College of Virginia Hospitals, Virginia Commonwealth University, Richmond, VA (DK62531): PI: Robert A. Fisher, MD, FACS; Co-PI: R.Todd Stravitz, MD; Study Coordinators: April Ashworth, RN; Andrea Lassiter, BS
National Institute of Diabetes and Digestive and Kidney Diseases, Division of Digestive Diseases and Nutrition, Bethesda, MD: James E. Everhart, MD, MPH; Leonard B. Seeff, MD; Patricia R. Robuck, PhD; Jay H. Hoofnagle, MD
1Presented in part at the 59th annual meeting of the American Association for the Study of Liver Diseases, San Francisco, California, November, 2008.
2Supported in part by the National Institutes of Health (NIDDK grant numbers U01-DK62536, U01-DK62444, U01-DK62467, U01-DK62483, U01-DK62484, U01-DK62494, U01-DK62496, U01-DK62498, U01-DK62505, U01-DK62531), the American Society of Transplant Surgeons, and the U.S. Department of Health and Human Services, Health Resources and Services Administration.
3This is publication number 14 of the Adult-to-Adult Living Donor Liver Transplantation Cohort Study.