Search tips
Search criteria 


Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Liver Transpl. Author manuscript; available in PMC 2014 March 1.
Published in final edited form as:
PMCID: PMC3600052

Functional Elements Associated with Hepatic Regeneration in Living Donors after Right Hepatic Lobectomy1,2


We quantified rates of hepatic regeneration and functional recovery for 6 months after right hepatic lobectomy in living donors for liver transplantation.

Twelve donors were studied at baseline; eight retested at (mean±SD) 11±3 days (T1), 10 at 91±9 days (T2), and 10 at 185±17 days (T3) after donation. Liver and spleen volumes were measured by computed tomography (CT) and single photon emission computed tomography (SPECT). Hepatic metabolism was assessed from caffeine and erythromycin, and hepatic blood flow from cholates, galactose, and perfused hepatic mass (PHM, by SPECT).

Regeneration rates (mL liver per kg body weight per day) were 0.60±0.22 from baseline to T1, 0.05±0.02 from T1 to T2, 0.01±0.01 from T2 to T3 by CT, 0.54±0.20, 0.04±0.01 and 0.01±0.02 by SPECT. At T3, liver volume was 84±7% of baseline by CT and 92±13% by SPECT. Changes in hepatic metabolism did not achieve statistical significance. At T1, unadjusted clearance ratios relative to baseline were 0.75±0.07 for intravenous cholate (p=0.0001), 0.88±0.15 for galactose (p=0.0681), 0.84±0.08 (p=0.002) for PHM, and 0.83±0.19 (p=0.056) for estimated hepatic blood flow. These ratios approached 1.00 by T3. At T1, ratios adjusted per L liver were 20%-50% greater than baseline and trended toward baseline by T3. Several findings were consistent with alteration of the portal circulation: increased cholate shunt, increased spleen volume, decreased platelet count, and decreased clearance of orally-administered cholate.

During the first 2 weeks after donation, hepatic regeneration is rapid and accounts for nearly two-thirds of total regeneration. Increases in hepatic blood flow and uptake of cholate characterize the early phase of regeneration. Right lobe donation alters the portal circulation of living donors, but long-term clinical consequences, if any, are unknown.

Keywords: cholate, SPECT liver-spleen scan, erythromycin, caffeine, galactose

Donor safety and outcome are the chief concerns of programs performing living donor liver transplantation (1,2). For adult recipients, a right lobe graft may be preferred over left lobe grafts due to the larger hepatic mass and anatomic orientation of vascular and biliary structures. For donors, a consequence of donating the right lobe graft is a relatively small remnant of residual liver from which to regenerate their liver mass. Even though hepatic regeneration permits donors to tolerate these resections, typically uneventfully, transient hepatic impairment is common, and hepatic failure, although rare, has been described (1-3).

In animal models, hepatic regeneration after resection of an otherwise normal liver is rapid, and usually complete within a few weeks (4,5). In these models, survival is linked to rate and completeness of regeneration and restoration of hepatic function.

Less is known about hepatic regeneration, hepatic function, and clinical outcomes in humans. Humar and colleagues measured liver volumes by computed tomography (CT) at 3 months post-donation and found that donor liver volume was 78.6% of ideal, whereas recipient liver volume was 103.9% of ideal (6). Nadalin measured the volumes of donor remnants by magnetic resonance imaging (MRI) and found that remnant volumes were 39% of baseline immediately after resection, increased to 77% by 3 months, and were 83% of baseline at 1 year after donation (7). Pomfreit and colleagues performed CT studies at baseline and 1 week and 1, 3, 6, and 12 months post-donation (8). By 1 year, liver volume was 83.3% of baseline, and female donors had significantly less regeneration compared with male donors (79.8 vs. 85.6%, p=0.01). These studies suggest that the regeneration of donor remnants is incomplete.

Some studies have also evaluated the impact of donation on hepatic function. Nadalin studied galactose elimination capacity (GEC) and found that unadjusted GEC had declined 50% by day 10, but had returned to baseline at subsequent time points (7). GEC adjusted for volume of remnant liver declined by less than 25% by day 10, was increased above baseline at days 90 and 180, and returned to baseline by day 360. Jochum (9) had results similar to Nadalin – GEC, expressed per kg body weight, was 50% lower than baseline at day 10 and nearly at baseline by day 90. Jochum also observed that indocyanine green (ICG) half-life increased and lidocaine half-life was not significantly altered (9). Neither study measured a broad array of liver functions nor did they examine the relationships of function to regeneration.

In our study, we measured multiple hepatic functions, hepatic blood flow, total liver and perfused liver volumes, and related these results to regeneration of the remnant left lobe during the first 6 months after right lobe donation.



Donors were approached for participation in this study only after they had undergone a full evaluation for living donor liver transplantation, were approved by the Selection Committee for liver transplantation, and the date of the operation was scheduled. Donors were recruited from two Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL) clinical centers – University of Colorado, Denver and University of California, San Francisco.

The protocol was approved by the Institutional Review Boards at the participating institutions, and all subjects provided written informed consent for both the main A2ALL study and this A2ALL-approved ancillary study.

Procedures, Test Compounds, and Analytical Methods

Participants maintained a caffeine-free, grapefruit juice-free, and alcohol-free diet for 3 days and were studied in the morning after an overnight fast in the General Clinical Research Centers (GCRC) of the participating centers. An indwelling intravenous 20-gauge catheter was placed for administration of test compounds and sampling blood. Patients were supine during the study and minimized their activity.

Hepatic metabolism was quantified using erythromycin (10) and caffeine (11) as test compounds.

Erythromycin breath test (EBT)

Three μCi of [14C-N-methyl] erythromycin (Metabolic Solutions Inc, Nashua, NH, product #: 02410806, IND: 31,760) was administered intravenously with a bolus injection followed by a 10 ml normal saline flush. Breath samples for measurement of 14CO2 generated from the hepatic metabolism of erythromycin were collected at baseline and 20 minutes after dose administration using a T-tube apparatus, capture solution, and indicator dye (12). 14CO2 was quantified by radioscintigraphy and percentage of erythromycin metabolized per hour determined.

Caffeine elimination rate (Caff kelim) and clearance (Caff Cl)

Caffeine, 300 mg (Ruger Chemical Co., Irvington, NJ, product number 0072-5, IND 65,175), was administered orally and its hepatic metabolism determined from clearance measured by high-performance liquid chromatography (HPLC) of saliva samples obtained at 2, 4, 8, and 12 hours after dosing. Volume of distribution (Vd) and kelim were determined by linear regression of loge concentration versus time and Cl was the product of Vd multiplied by kelim.

The hepatic circulation was quantified using test compounds with flow-dependent, high first-pass hepatic extraction (galactose (13), cholates (14-17), 99mTc-cis-sulfur colloid (15-18).

Galactose elimination capacity (GEC)

Galactose, 30 g of low endotoxin D-galactose (Pfanstiehl Laboratories, Inc., Waukegan, IL, product number G-105-1, IND 65107), in 100 mL sterile water was administered intravenously over 5 minutes. Blood samples were obtained at baseline and 20, 40, 60, and 80 minutes after dosing and galactose concentration quantified by spectrophotometry using a standardized kit (Lactose/D-galactose kit, Boehringer Mannheim Cat. No. 176 303). GEC is the slope from the linear regression of concentration versus time.

Cholate clearances (CA Cl) and shunt (CA shunt)

Dual isotopes of cholate were simultaneously administered in anionic form in bicarbonate solutions, one orally and the other intravenously (14-17). The oral solution contained 40 mg of 2,2,4,4-2H cholate (CDN Isotopes Inc. Quebec Canada, product # D-2452, studied under IND 65123) plus 600 mg NaHCO3 in apple or grape juice. The intravenous solution contained 20 mg 24-13C cholate (CDN Isotopes Inc. Quebec Canada, product # C-3448, studied under IND 65121) dissolved in 5 mL of USP grade NaHCO3, 1meq/mL (Baxter HealthCare, Tarrytown, NY). This solution was mixed with 5 mL of USP grade 25% human serum albumin (Bayer HealthCare Tarrytown, NY 10591 NDC# 0026-0692-16) and administered via antecubital vein over 1 minute. Blood samples were obtained at baseline and at 5, 20, 45, 60, and 90 minutes after dosing (14) and cholate isotopes quantified by LC/MS. CA Cloral and CA Cliv were calculated from dose (40 mg oral or 20 mg intravenous) divided by area under the concentration versus time curves for each isotope (mg*min/mL) and normalized for body weight (kg), and CA shunt was the ratio of clearances of the intravenously to orally-administered isotopes. Estimated hepatic blood flow was calculated from the equation, CA Cliv/((1-shunt/100)*(1-hematocrit)). An example of a pair of studies from one donor of dual cholate clearance studies prior to and after donation is shown in Figure 1.

Figure 1
Example of clearances of cholates before and after donation

SPECT liver-spleen scan

After completion of blood sampling for the galactose and cholate tests, patients ingested a standard meal and 375 ml Ensure (Abbott Laboratories, Abbott Park, IL) at 30 minutes prior to intravenous administration of 5 to 6 mCi of 99mTc-cis-sulfur colloid (2 to 12 micron particle size, CIS-US, Inc., Bedford, MA) for SPECT (15-18). SPECT studies were performed at the two clinical sites and data transferred to UC Irvine for processing (JCH, NM). Perfused hepatic mass (PHM) calculated from these images quantified the relative distribution of sulfur colloid between liver, spleen and bone marrow. Volumes of liver and spleen were also determined (16-20).

Organ volumes and rates of hepatic regeneration were measured by both CT and SPECT liver-spleen scan.

Volumes from CT/MRI

CT studies and SPECT liver-spleen scan were performed on different days. Liver and spleen volumes were determined from the standard CT software algorithms used by the Radiology Departments at participating clinical sites.

Volumes from SPECT

Liver and spleen volumes were also calculated from the SPECT reconstruction of images using the method of Hoefs (16-20). Volume was derived from total counts in liver and spleen from regions of interest around the summarized transaxial image, a representative organ concentration from a single transaxial slice, and dividing the total hepatic or splenic counts by a representative concentration.

Hepatic regeneration rates were defined by ΔV/Δt, from both CT and SPECT, where ΔV was the change in hepatic volume between consecutive time points and Δt the time interval. Baseline (B) volume was the liver volume measured prior to donation. Remnant liver volume on the day of donation (T0) was determined from baseline CT by subtracting the estimated right lobe graft from total liver. For SPECT, we assumed the same proportionate size of remnant relative to baseline as was estimated from CT. Regeneration rates were determined for the intervals from T0 to T1, T1 to T2, and T2 to T3.

Clearance tests were expressed relative to body size (per kg) or liver size (per L liver). Changes in hepatic metabolism (microsomal function) were estimated from the serial changes in caffeine clearance (CYP1A2) and the erythromycin breath test (CYP3A4). Changes in total hepatic blood flow were estimated from the serial changes in galactose elimination capacity, clearance of intravenously-administered 24-13C cholate, and SPECT liver-spleen scan. Alteration of the portal circulation was assessed by the changes from baseline in clearance of orally-administered 2,2,4,4-2H cholate, cholate shunt, PHM from SPECT liver spleen scan, platelet count, and spleen volume.

Statistical Analyses

Results are expressed as means, standard deviations, and ranges. Differences between baseline and post-donation results at T1, T2, and T3, and differences between post-baseline time points, were compared using 2-sided paired t-tests. To test the relationship between platelet counts and spleen size, we used both linear regression and mixed model regression with subjects as random effects. Statistical analyses were performed at the Data Coordinating Center for A2ALL (University of Michigan) using SAS release 9.2 (SAS Institute, Cary, NC).


Twelve donors were studied at baseline (B); eight were retested at 11±3 days (T1), ten at 91±9 days (T2), and ten at 185±17 (T3) days after surgery. The mean age was 38 years (range 21 to 54 years), body mass index (BMI) 25.2±2.8, sex 4M:8F, and 10 were white.

Standard Laboratory Tests

Table 1 displays the changes in routine laboratory tests over time after donation. All laboratory values were normal at baseline. At T1, bilirubin, INR, and ALT were higher and albumin lower than baseline values. By T2, these tests were trending toward baseline and at T3, all had returned to baseline values.

Table 1
Laboratory values before and after donation

Total Liver versus Perfused Liver Volume

Volumes by CT are larger than those measured by SPECT. Linear regression through the origin of CT versus SPECT volumes, using data from all time points, indicated that liver volumes by CT/MRI were approximately 22% larger (slope 1.22, r = 0.93, p<0.0001) and spleen volumes 4% larger when compared with SPECT (slope 1.04, r = 0.95, p<0.0001). Ratios of perfused liver volume (by SPECT) to total liver volume (by CT) were constant during regeneration (0.84 to 0.86), although slightly greater than the ratio at baseline (0.78).

Regeneration Rates

Liver volumes at each time point (mL and mL/kg), reconstitution of baseline volume (Vt/Vpre-donation), and rates of regeneration (mL kg-1 d-1) are given in Table 2. The relative changes in these parameters during regeneration were similar between CT and SPECT. Total liver volumes by CT at each time point (T0 through T3), relative to pre-donation volumes, are shown for each donor in Figure 2, Panel A.

Figure 2
Liver and spleen volume ratios (compared with baseline pre-donation) by time since donation
Table 2
Hepatic regeneration: Liver volumes (V) before and after donation

There were at least two phases of regeneration – a rapid early phase during the first 2 weeks and a slower later phase after the first 2 weeks. Based on CT, regeneration rates were 0.60±0.22 mL kg-1d-1 from T0 to T1, 0.05±0.02 mL kg-1d-1 from T1 to T2, and 0.01±0.01 mL kg-1d-1 from T2 to T3 (Table 2). Based on SPECT, regeneration rates were similar: 0.54±0.20 mLkg-1d-1 from T0 to T1, 0.04±0.01 mL kg-1d-1 from T1 to T2, and 0.01±0.02 mL kg-1d-1 from T2 to T3 (Table 2).

Approximately two-thirds of total hepatic regeneration occurred within the first 2 weeks after donation, and there was minimal regeneration after 3 months. At T3, approximately 6 months after donation, liver volumes were 84±7% of baseline by CT and 92±13% of baseline by SPECT (Table 2).

Hepatic Metabolism

Changes in hepatic metabolism from pre-donation baseline are shown in Table 3. Total clearances of caffeine and erythromycin were slightly lower than baseline at T1; and slightly greater than baseline by T2 and T3. After adjusting for liver volume, clearances of caffeine and erythromycin were increased above baseline at T1, and this increase persisted through T2 and T3. However, none of these changes in metabolism were statistically significant.

Table 3
Hepatic metabolism before and after donation

Hepatic Blood Flow

Total clearances of galactose, intravenous cholate, and SPECT, and calculated total hepatic blood flow are displayed in Table 4. These tests reflect the total blood flow to the remnant. At T1, total clearance of galactose (GEC) was 0.88±0.15 of pre-donation baseline (p=0.0681), cholate after intravenous administration (CA Cliv) 0.75±0.07 of baseline (p=0.0001), and 99mTc-cis-sulfur colloid (SPECT) 0.84±0.08 of baseline (p=0.002). Total hepatic blood flow had decreased to 0.83±0.19 of baseline (p=0.056). Thus, by three very different methods (GEC, dual cholate clearance, and SPECT) we demonstrated, unadjusted for liver volume, a consistent moderate decrease in total clearance and hepatic blood flow at T1.

Table 4
Parameters of hepatic blood flow (HBF)

Although the total clearances of flow-dependent compounds were reduced at T1, clearances adjusted for liver volume, expressed per L liver, were increased at T1 (Table 4). Clearances per L liver of galactose, intravenous cholate, and 99mTc-cis-sulfur colloid (estimated change in HBF) were all increased above baseline. These findings suggest that the early rapid phase of regeneration is associated with enhanced blood flow per unit of regenerating liver.

Orally-administered cholate is delivered to the portal circulation after its absorption from the intestine – changes in the clearance of orally-administered cholate reflect changes in clearance from the portal circulation. Like intravenous cholate, total clearance of orally-administered cholate is decreased at T1, reflecting the reduced hepatic mass. But, unlike intravenous cholate, clearance per L liver of orally-administered cholate did not increase above baseline at T1 (Table 5). The selective increase in clearance per L liver of intravenously-administered cholate, is consistent with selective enhancement of hepatic arterial flow during the early phase of regeneration.

Table 5
Measures reflecting changes in the portal circulation before and after donation

First Pass Uptake of Cholate

We estimated first-pass uptake of cholate from the fraction of the oral dose escaping hepatic extraction, corrected for the administered dose of cholate and normalized to liver volume. At T1, during the period of rapid regeneration, we found a significant increase in cholate uptake (B vs. T1, mg/L liver: 21±5 vs. 31±9, p=0.017). Cholate uptake at T2 (25±4, p=0.034) and T3 (24±6, p=0.058) approached baseline values.

Alteration of the Portal Circulation

Several of our test results suggested that the portal circulation is altered after right lobe donation (Table 5). At T1, the total clearance of orally-administered cholate decreased (p=0.0006), cholate shunt increased (p=0.03), and platelet count decreased (p=0.07). These changes persisted at T2, but, except for platelet count, trended toward normal by T3.

Paralleling the changes in platelet count, spleen volumes by both CT and SPECT increased by T1. Spleen volume did not increase further, declined slightly, but remained above baseline throughout (Figure 2, Panel B and Table 5). By T3, 6 months after donation, CT spleen volume remained at 127±17% of baseline (p=0.0009) and SPECT spleen volume remained at 150% of baseline (p=0.015). Platelet count at T1 was 14% lower than baseline and remained decreased through T3 (Table 5). Platelet count was inversely related to spleen volume (Figure 3). This relationship was significant both unadjusted (p=0.0001) or adjusted (p=0.0018) for subject effects with a mixed model.

Figure 3
Platelet count and spleen volume per kg body weight before and after donation


This prospective study examined the longitudinal changes in multiple hepatic functions after donation of the right hepatic lobe by living donors, and uniquely related functional changes to the regeneration of the left lobe remnant. Ten of the 12 donors we studied had an uncomplicated post-operative course as indicated by standard laboratory tests and lack of clinical complications. For the two with complications, one had a Grade 2 urinary tract infection, and the other had a Grade 1 pleural effusion and a Grade 2 wound infection, all in the first month post-donation. Thus, our results of hepatic imaging, volume determinations, and function testing may likely apply to other donors undergoing a right hepatic lobectomy with an uncomplicated or modestly complicated course.

We observed differences in liver volumes related to the differences in imaging between CT and SPECT. CT images include all structures within the region of interest, including vascular, connective tissue, and biliary structures. SPECT images are based on phagocytosis of 99mTc-cis-sulfur colloid by the reticuloendothelial system and exclude nonparenchymal structures. The 22% lower volume measured by SPECT likely reflects its selectivity for parenchyma and the perfused hepatic mass.

Rates of regeneration varied with time following hepatic lobectomy. After lobectomy, the residual left lobe remnant was 31% of baseline hepatic volume by CT/MRI. In the first 2 weeks post-donation, hepatic volume nearly doubled, and regeneration rate was 0.60 mL d-1 kg-1 body weight by CT/MRI and 0.54 mL d-1 kg-1 body weight by SPECT. Regeneration slowed dramatically after the first 2 weeks. During the following approximate 3 months, regeneration was only 0.05 mL d-1 kg-1 body weight by CT/MRI and 0.04 mL d-1 kg-1 body weight by SPECT. Regeneration rate was even slower between 3 (T2) and 6 months (T3). Consistent with other studies (6-9), hepatic regeneration in donors was incomplete. At 6 months post-donation, donors achieved only 84% (CT/MRI) to 92% (SPECT) of their baseline hepatic volume. The dramatic differences in regeneration rates between time intervals suggests that factors regulating hepatic growth and, ultimately, final liver volume must vary considerably between the early and later phases of regeneration.

The rapid early phase of rapid hepatic regeneration, from baseline to T1, was associated primarily with two functional changes – enhancement of hepatic blood flow per gram of hepatic tissue and increase in the hepatic uptake of cholate. Naturally, the total hepatic blood flow must decrease with removal of 60% of hepatic tissue, but the liver compensates by increasing local flow. Hepatic blood flow per L liver was assessed by three independent measurements that indicated a ~30% to 50% increase in tissue blood flow. Thus, the blood flow per L tissue increased helping to preserve blood flow dependent hepatic function and partially compensate for the decrease in total hepatic mass.

In contrast to the increase in hepatic flow per L liver, the clearance of orally-administered cholate per L liver, a marker of portal inflow, did not change. Taken together, these observations suggest that the enhancement of hepatic blood flow is likely related to selective recruitment of oxygen-rich hepatic arterial inflow. The importance of arterial perfusion in hepatic regeneration was emphasized recently in a rat model of ischemic injury (21). In the latter model, hepatic arterial perfusion determined not only the extent of hepatic necrosis but also the formation of vascularized sinusoidal channels and parenchymal recovery.

Another unique finding of our study was selective enhancement of hepatic uptake of orally-administered cholate during early rapid hepatic regeneration. In animal models, activation of the primary nuclear bile acid receptor farnesoid X receptor (FXR), by the hepatic flux of bile acids accelerates regeneration and inhibits genes of metabolism (22-24). Thus, it is of interest that we measured a specific increase in hepatic uptake of cholate during the early rapid phase of hepatic regeneration. We speculate that enhanced cholate uptake during the early phase of regeneration in living donors supports a role for bile acids in the regulation of human hepatic regeneration.

We did not observe statistically significant changes in the clearance or metabolism of two substrates of the cytochrome P450 system, caffeine and erythromycin. The immediate effect of hepatic resection is reduction in total hepatic metabolic capacity (25). Our results indicated that by 11±3 days post-donation, hepatic metabolic capacity had returned toward baseline and the metabolism of both caffeine and erythromycin per L liver had increased – consistent with compensatory up-regulation of hepatic cytochrome P450 enzymes. A study examining the acute phase response of cytochrome P450 enzymes after LDLT found early reduction at day 3-4 in EBT with a return to near baseline around day 10 (26). Nonetheless, in the first several days post-donation, it is likely that donors have a reduced total metabolic capacity due to loss of hepatocyte mass and the immediate regenerative process (22-25). A clinical point worth emphasizing is that dosing of medications cleared by hepatic metabolism should be adjusted downward to avoid excessive accumulation and toxicity during the first 1 to 2 weeks after donor hepatectomy.

An important observation of our study with potential clinical implications was evidence pointing to an alteration of the portal circulation. Cholate shunt is a real-time measure of events in the portal circulation. There was an initial perturbation of portal circulation with increased cholate shunt which then trended toward normal by T2 and was at or near baseline by T3. Other findings indicated a persistently altered portal circulation. Spleen volume increased by T1, trended downward by T2 and T3, but remained significantly above baseline at T3. The increase in spleen size was associated with decreased platelet count – indeed we found a significant inverse correlation of platelet count to spleen volume.

Others have also noted a relationship between platelet count and spleen size after living donation (25,27,28). In these studies, the reduction in platelet count was associated with normal or elevated levels of thrombopoeitin (29). These findings and our results are consistent with hypersplenism from persistence of an altered portal circulation and portal hypertension and suggests that long-term follow-up of donors and evaluation for manifestations of an altered portal circulation or portal hypertension may be warranted.

We conclude that there are at least two phases of hepatic regeneration. The early rapid phase of regeneration lasts for 2 weeks, accounts for two-thirds of total regeneration, and is associated with recruitment of hepatic arterial inflow and enhanced uptake of bile acids. Right hepatic lobectomy alters the portal circulation, some of the changes reverse but others persist. Although the clinical implications of these findings are unknown, further long-term studies of the portal circulation of donors may be warranted.


The authors wish to acknowledge the contributions of our co-investigators, study coordinators, and staff at each of the participating institutions: Jennifer DeSanto RN, Rita Lerner, Michelle Jaramillo at University of Colorado Denver, Aurora, CO; Jenifer Twiford, RN at University of California San Francisco, San Francisco, CA, Dulce MacLeod, RN at University of California San Francisco, San Francisco, CA; Carrie Nielsen at University of North Carolina, Chapel Hill, NC; Peg Hill-Callahan, Katherine Baisden, and Terese Howell at University of Michigan, Ann Arbor, MI; Jay H. Hoofnagle and Leonard Seeff at National Institute of Diabetes and Digestive and Kidney Diseases, Division of Digestive Diseases and Nutrition, Bethesda, MD; and, members of the Data and Safety Monitoring Board for A2ALL.

Financial Disclosures: G. T. Everson has intellectual property rights related to the University of Colorado Denver filing of US Patent Application No. 60/647,689, “Methods for Diagnosis and Intervention of Hepatic Disorders”, 26 January 2005, and International Application Number PCT/US2006/003132 as published under the Patent Cooperation Treaty, World Intellectual Property Organization, International Patent Classification A61K 49/00 (2006.01), International Publication Number WO 2006/081521 A2, 3 August 2006 (03.08.2006).

List of Abbreviations

Adult-to-Adult Living Donor Liver Transplantation Cohort Study
alanine aminotransferase
aspartate aminotransferase
body mass index
erythromycin breath test
General Clinical Research Center
galactose elimination capacity
Investigational New Drug
prothrombin time international normalized ratio
elimination rate constant
liquid chromatography–mass spectrometry
living donor liver transplantation
perfused hepatic mass
quantitative liver function tests
standard deviation
single photon emission computed tomography



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, M.D.; Co-PI, Robert S. Brown Jr, M.D., M.P.H.; study coordinators, Scott Heese, B.A., and Jonah S. Zaretsky, B.A.

Northwestern University, Chicago, IL (DK62467): PI Michael M. I. Abecassis, M.D., M.B.A.; Co-PI Laura M. Kulik, M.D.; study coordinator, Patrice Al-Saden, R.N., C.C.R.C.

University of Pennsylvania Health System, Philadelphia, PA (DK62494): PI Abraham Shaked, M.D., Ph.D.; Co-PI Kim M. Olthoff, M.D.; study coordinators, Brian Conboy, P.A., M.B.A., and Mary Shaw, R.N., B.B.A.

University of Colorado Health Sciences Center, Denver, CO (DK62536): PI Gregory T. Everson, M.D.; Co-PI Igal Kam, M.D.; study coordinators, Carlos Garcia, B.S., and Anastasia Krajec, R.N.

University of California Los Angeles, Los Angeles, CA (DK62496):PI Johnny C. Hong, M.D.; Co-PI Ronald W. Busuttil, M.D., Ph.D.; study coordinator, Janet Mooney, R.N., B.S.N.

University of California San Francisco, San Francisco, CA (DK62444): PI Chris E. Freise, M.D., F.A.C.S.; Co-PI Norah A. Terrault, M.D.; study coordinator, Dulce MacLeod, R.N.

University of Michigan Medical Center, Ann Arbor, MI (DK62498): PI Robert M. Merion, M.D.; data coordinating center staff, Anna S. F. Lok, M.D., Akinlolu O. Ojo, M.D., Ph.D., Brenda W. Gillespie, Ph.D., Margaret Hill-Callahan, B.S., L.S.W., Terese Howell, B.S., A.C.R.P., Lisa Holloway, B. S., A.C.R.P., Monique Lowe, B.S., Abby Smith, B.A., and Abby Brithinee, B.A.

University of North Carolina, Chapel Hill, NC (DK62505): PI Paul H. Hayashi, M.D., M.P.H.; study coordinator, Tracy Russell, M.A.

University of Virginia (DK62484): PI Carl L. Berg, M.D.; study coordinator, Jaye Davis, R.N.

Medical College of Virginia Hospitals, Virginia Commonwealth University, Richmond, VA (DK62531): PI Robert A. Fisher, M.D., F.A.C.S.; Co-PI R. Todd Stravitz, M.D.; study coordinators, April Ashworth, R.N., and Andrea Lassiter, B.S.

Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD: James E. Everhart, M.D.,M.P.H., Averell Sherker, M.D., and Jay H. Hoofnagle, M.D.

Heather Van Doren, MFA, a senior medical editor with Arbor Research Collaborative for Health, provided editorial assistance on this manuscript.


1This is publication number 20 from the Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL Study Group). A2ALL was registered with clinicaltrials .gov (NCT00096733).

2Financial Support: This study was supported by the National Institute of Diabetes, Digestive & Kidney Diseases, National Institutes of Health, Bethesda, MD (NIDDK grant numbers: U01-DK62536, U01-DK62444, U01-DK62467, U01-DK62483, U01-DK62484, U01-DK62494, U01-DK62496, U01-DK62498, U01-DK62505, U01-DK62531) and University of California – Irvine, Irvine, CA (contract 38643).

In addition to the above named institutions, the A2ALL Study Group also includes Northwestern University, Chicago, IL; University of California – Los Angeles, CA; University of California – San Francisco, CA; University of Colorado Health Sciences Center, Denver, CO; University of North Carolina, Chapel Hill, NC; University of Pennsylvania, Philadelphia, PA; Virginia Commonwealth University, Richmond, VA.

Conflicts of Interest G. T. Everson has equity interest in HepQuant LLC.

Authors with no financial relationships to disclose are: J. Hoefs, C. Niemann, K. Olthoff, R. Dupuis, S. Lauriski, A. Herman, N. Milne, B. Gillespie, N. Goodrich, J. Everhart.

Contributions of Authors: Gregory T. Everson and Claus U. Niemann were principal investigators at the two clinical centers at the University of Colorado and University of California San Francisco, respectively. John C. Hoefs and Norah Milne were responsible for the analyses of SPECT liver-spleen scans. Kim Olthoff participated in preparation of the manuscript. Robert Dupuis analyzed the erythromycin breath tests and Shannon Lauriski analyzed the cholate clearances and shunt and caffeine and galactose samples. Andrea Herman was study coordinator at Colorado. Brenda Gillespie and Nathan Goodrich performed the statistical analyses. James Everhart was the project officer from NIDDK, NIH.


1. Trotter JF, Adam R, Lo CM, Kenison J. Documented Deaths of Hepatic Lobe Donors for Living Donor Liver Transplantation. Liver Transplantation. 2006;12:1485–1488. [PubMed]
2. Ghobrial RM, Freise CE, Trotter JF, Tong L, Ojo AO, Fair JH, et al. Donor Morbidity After Living Donation for Liver Transplantation. Gastroenterology. 2008;135:468–476. [PMC free article] [PubMed]
3. Trotter JF, Gillespie BW, Terrault NA, Abecassis MM, Merion RM, Brown RS, Jr, et al. Laboratory Test Results After Living Liver Donation in the Adult-to-Adult Living Donor Liver Transplantation Cohort Study. Liver Transplantation. 2011;17:409–417. [PMC free article] [PubMed]
4. Dezső K, Papp V, Bugyik E, Hegyesi H, Sáfrány G, Bödör C, et al. Structural analysis of oval-cell-mediated liver regeneration in rats. Hepatology. 2012 Mar 15; doi: 10.1002/hep.25713. [Epub ahead of print] [PubMed]
5. Seki T, Yokoyama Y, Nagasaki H, Kokuryo T, Nagino M. Adipose tissue-derived mesenchymal stem cell transplantation promotes hepatic regeneration after hepatic ischemia-reperfusion and subsequent hepatectomy in rats. J Surg Res. 2012 Mar 28; [Epub ahead of print] PMID: 22482751 [PubMed - as supplied by publisher] [PubMed]
6. Humar A, Kosari K, Sielaff TD, Glessing B, Gomes M, Dietz C, et al. Liver Regeneration After Adult Living Donor and Deceased Donor Split-Liver Transplants. Liver Transplantation. 2004;10:374–378. [PubMed]
7. Nadalin S, Testa G, Malago M, Beste M, Frilling A, Schroeder T, et al. Volumetric and Functional Recovery of the Liver After Right Hepatectomy for Living Donation. Liver Transplantation. 2004;10:1024–1029. [PubMed]
8. Pomfret EA, Pomposelli JJ, Gordon FD, Erbay N, Price LL, Lewis WD, et al. Liver Regeneration and Surgical Outcome in Donors of Right-Lobe Liver Grafts. Transplantation. 2003;76:5–10. [PubMed]
9. Jochum C, Beste M, Penndorf V, Farahani MS, Testa G, Nadalin S, et al. Quantitative Liver Function Tests in Donors and Recipients of Living Donor Liver Transplantation. Liver Transplantation. 2006;12:544–549. [PubMed]
10. Schmidt LE, Olsen AK, Stentoft K, Rasmussen A, Kirkegaard P, Dalhoff K. Early postoperative erythromycin breath test correlates with hepatic cytochrome P4503A activity in liver transplant recipients. Clin Pharmacol Ther. 2001;70:446–454. [PubMed]
11. Wahllander A, Mohr S, Paumgartner G. Assessment of hepatic function. Comparison of caffeine clearance in serum and saliva during the day and at night. J Hepatol. 1990;10:129–137. [PubMed]
12. Watkins PB, Murray SA, Winkelman LG, Heuman DM, Wrighton SA, Guzelian PS. Erythromycin breath test as an assay of glucocorticoid-inducible liver cytochromes P-450. Studies in rats and patients. J Clin Invest. 1989;83:688–697. [PMC free article] [PubMed]
13. Keiding S. Galactose clearance measurements and liver blood flow. Gastroenterology. 1988;94:477–481. [PubMed]
14. Everson GT, Martucci MA, Shiffman ML, Sterling RK, Morgan TR, Hoefs JC, et al. Portal-systemic shunting in patients with fibrosis or cirrhosis due to chronic hepatitis C: the minimal model for measuring cholate clearances and shunt. Aliment Pharmacol Ther. 2007;26:401–410. [PubMed]
15. Everson GT, Shiffman ML, Morgan TR, Hoefs JC, Sterling RK, Wagner DA, et al. The spectrum of hepatic functional impairment in compensated chronic hepatitis C: results from the Hepatitis C Anti-viral Long-term Treatment against Cirrhosis Trial. Aliment Pharmacol Ther. 2008;27:798–809. [PubMed]
16. Everson GT, Shiffman ML, Hoefs JC, Morgan TR, Sterling RK, Wagner DA, et al. Quantitative tests of liver function measure hepatic improvement after sustained virological response: results from the HALT-C Trial. Aliment Pharmacol Ther. 2009;29:589–601. [PMC free article] [PubMed]
17. Everson GT, Shiffman ML, Hoefs JC, Morgan TR, Sterling RK, Wagner DA, et al. Quantitative liver function tests improve the prediction of clinical outcomes in chronic hepatitis C: Results from the HALT-C Trial. Hepatology. 2012;55:1019–1029. [PMC free article] [PubMed]
18. Hoefs JC, Wang F, Kanel G. Functional measurement of the non-fibrotic hepatic mass in cirrhotic patients. Am J Gastroenterol. 1997;92:2054–2058. [PubMed]
19. Hoefs JC, Sheikh MY, Guerrero H, Milne N. Factors Affecting the Quantitative Liver-Spleen Scan in Normal Individuals. Dig Dis Sci. 2005;50:283–289. [PubMed]
20. Hoefs JC, Wang FW, Walker B, Kanel G. A novel, simple method of functional spleen volume calculation by liver-spleen scan. J Nuc Med. 1999;40:1745–1755. [PubMed]
21. Huang H, Deng M, Jin H, Liu A, Dirsch O, Dahmen U. Hepatic Arterial Perfusion is Essential for the Spontaneous Recovery from Focal Hepatic Venous Outflow Obstruction in Rats. Am J Transplant. 2011 Aug 10; Doi: 10.1111/j.1600-6143.2011.03682.x. [Epub ahead of print] [PubMed]
22. Milona A, Owen BM, van Mil S, Dormann D, Mataki C, Boudjelal M, et al. The normal mechanisms of pregnancy-induced liver growth are not maintained in mice lacking the bile acid sensor FXR. Am J Physiol Gastrointest Liver Physiol. 2010;298:G151–G158. [PubMed]
23. Chen WD, Wang YD, Meng Z, Zhang L, Huang W. Nuclear bile acid receptor FXR in the hepatic regeneration. Biochim Biophys Acta. 2011;1812:888–892. [PubMed]
24. Geier A, Trautwein C. Bile acids are “homeotrophic” sensors of the functional hepatic capacity and regulate adaptive growth during liver regeneration. Hepatology. 2007;45:251–253. [PubMed]
25. Schumann R, Bonney I, McDevitt LM, Cooper JT, Cepeda MS. Extent of right hepatectomy determines postoperative donor albumin and bilirubin changes: new insights. Liver Int. 2008;28:95–98. [PubMed]
26. Dupuis R, Williams E, Hawke R, Nelson A, Johnson M, Shrestha R. Cytochrome P450 activity and the acute phase response in healthy donors after living donor liver transplantation (LDLT). Hepatology. 2004;40(Suppl,S4):561A.
27. Chen TY, Chen CL, Huang TL, Tsang LL, Wang CC, Liu YW, et al. Spleen volume and platelet count changes among donors after living donor liver transplantation. Hepatogastroenterology. 2008;55:1211–1215. [PubMed]
28. Chen TY, Chen CL, Huang TL, Tsang LL, Wang CC, Wang SH, et al. Remnant liver regeneration and spleen volume changes after living liver donation: influence of the middle hepatic vein. Clin Transplant. 2006;20:725–731. [PubMed]
29. Nagasako Y, Jin MB, Miyazaki H, Nakayama M, Shimamura T, Furukawa H, et al. Thrombopoeitin in Postoperative Thrombocytopenia Following Living Donor Hepatectomy. Liver Transplantation. 2006;12:435–439. [PubMed]