ORIGINAL ARTICLES

Hepatocellular Proliferation and Changes inMicroarchitecture of Right Lobe Allografts in Adult

Transplant RecipientsRuoqing Huang,1 Thomas D. Schiano,2 May Jennifer Amolat,1 Charles M. Miller,2

Swan N. Thung,1 and Romil Saxena1

Imaging studies show complete restoration of liver vol-ume in adult recipients of right lobe allografts within 2–3weeks of living donor transplantation (LDLT). However,it is not known if this growth is associated with restorationof hepatic microarchitecture. We compared 21 biopsieswithout significant pathology from LDLT recipients with23 biopsies from adult recipients of cadaveric donor livertransplantation (CDLT) performed within 3 months oftransplantation. The difference in the number of portaltracts per cm was statistically significant (P < .0001)between CDLT (9.08 � 1.74) and LDLT recipientswithin 3 months (6.26 � 1.62), as well as after 3 monthsfollowing transplantation (6.56 � 1.44). The coefficientof correlation between length of biopsy specimens and thenumber of portal tracts in these 3 groups was .94, .93, and.85, respectively. Proliferative activity demonstrated byimmunohistochemical staining for MIB-1 was seen pre-dominantly in hepatocytes in both groups; bile ducts onlyoccasionally stained positive. The difference betweenlabeling indices of hepatocytes was statistically significant(P � .00056) between CDLT and LDLT recipients within3 months of transplantation (.82 � .63 and 4.53 � 3.72),and between LDLT recipients within 3 weeks and after 3weeks of transplantation (5.97 � 3.78 and 1.80 � 1.37,P � .0074). In conclusion, restoration of liver volumefollowing LDLT occurs by proliferation of hepatocytes inthe immediate posttransplant period. There is a decreasein number of portal tracts in these volume-restored allo-grafts. Volume restoration is therefore, not accompaniedby restoration of hepatic microarchitecture. (LiverTranspl 2004;10:1461–1467.)

The inability to effectively halt or reverse liver fibro-sis, enhance liver regeneration, or maintain liver

function with artificial support systems has establishedliver transplantation as a standard therapeutic modalityfor chronic and fulminant liver disease. However, whilethe number of available cadaveric organs has remainedrelatively constant over the decades, the number ofpatients on the transplant waiting list has grown expo-nentially, necessitating innovative ways to providefunctional organs. Transplantation of the right hepaticlobe from a healthy adult into another, or living donorliver transplantation (LDLT), which takes advantage ofthe immense proliferative capacity of the liver, is onesuch response to expanding the donor pool; this proce-

dure provides the added advantages of minimal preser-vation injury and availability of organs at an optimaltime for the recipient before liver decompensationoccurs.

Imaging studies show almost complete restorationof liver volume in adult recipients of right lobe allograftswithin 2–3 weeks of transplantation.1–3 However, thepathological correlates of this increase in mass and vol-ume have not been studied. The mechanisms by whichthe graft accomplishes restoration of volume and massare not known; more importantly, it is not knownwhether this restoration of volume and mass is accom-panied by restoration of hepatic microarchitecture thatis vital to normal long-term organ function. We soughtto elucidate the changes occurring in hepatic microar-chitecture after right lobe LDLT by comparing liverbiopsies from recipients of LDLT with those of cadav-eric donor liver transplantation (CDLT).

Materials and Methods

The database and records of the Department of Pathologyand the Recanati-Miller Transplantation Institute at MountSinai Hospital were reviewed to identify patients who hadreceived right lobe allografts from living donors and who hadbiopsies performed within 3 months of transplantation. Acomparison group was compiled of patients who had under-

Abbreviations: LDLT, living donor liver transplantation;CDLT, cadaveric liver transplantation.

From the 1Lillian and Henry M. Stratton–Hans Popper Depart-ment of Pathology and 2Recanati-Miller Transplantation Institute,Mount Sinai Medical Center, New York, NY.

Presented in part at the Liver Meeting, Dallas, October 2001, andpublished in abstract form in Hepatology 2001;34:296A.

Address reprint requests to Romil Saxena, M.D., FRCPath, Depart-ment of Pathology and Laboratory Medicine, UH 3465, Indiana Uni-versity School of Medicine, 550 N University Blvd, Indianapolis, IN46202. Telephone: 317 274 1721; FAX: 317 274 5346; E-mail:rsaxena@iupui.edu

Copyright © 2004 by the American Association for the Study ofLiver Diseases

Published online in Wiley InterScience (www.interscience.wiley.com).DOI 10.1002/lt.20293

1461Liver Transplantation, Vol 10, No 12 (December), 2004: pp 1461–1467

gone cadaveric whole liver transplantation and who also hadbiopsies during the first 3 months posttransplantation. Allbiopsy specimens had been obtained by a uniform procedureusing a Menghini needle with an inner diameter of 1.3 mm.In each group, pathology reports were reviewed to select thosebiopsies that showed either no pathologic change or minimalpathologic changes. A third group comprised follow-up biop-sies without significant pathologic changes in the LDLTgroup. The absence of significant pathologic changes wasconfirmed by review of all the selected biopsies by 2 patholo-gists (H.R., R.S.). These biopsies formed the case material forthe analysis. The biopsies had all been fixed in neutral buff-ered formalin, routinely processed for paraffin embedding,cut at 4 �m and stained with hematoxylin and eosin.

In each case, the length of the biopsy specimen was mea-sured and the total number of portal tracts was counted in 2histologic levels, and the number of portal tracts per cm ofliver tissue was obtained. The criteria used for identification ofportal tracts were based on the study by Crawford et al.,4 whofound portal dyads as commonly as portal triads in liver biop-sies from normal human adults. Portal triads were defined asstructures that contained at least 1 profile each of a hepaticartery, portal vein, and bile duct. A portal dyad contained 2 ofthese profiles, but not all 3. Both portal triads and portal dyadswere included in the total count of portal tracts. Incompleteportal tracts at the edge of the biopsy that contained at least 2profiles of bile duct, hepatic artery, and portal vein in anycombination (portal dyad) were counted as a portal tract.

Sections 4-�m thick were then cut from all biopsiesobtained within 3 months of transplantation and stained withthe proliferation marker, MIB-1 (1:20; DAKO, Carpenteria,CA) by a standard immunohistochemical procedure follow-ing antigen retrieval. The labeling index was calculated as thenumber of positively-stained nuclei per 1,000 hepatocytes. Atotal of 400 hepatocyte nuclei were counted manually withthe help of a hemacytometer cell counter. Statistical analyseswere performed using the SPSS statistics program (SPSS Inc.,Chicago, IL).

This study was approved by the Institutional ReviewBoard of the Mount Sinai Medical Center.

Results

A total of 21 patients were identified who had receivedright lobe liver allografts from living donors, and whohad liver biopsies during the first 3 months post-LDLTthat did not show significant pathologic changes. Thecomparison group consisted of 23 patients who hadreceived cadaveric whole liver allografts, and who hadbiopsies during the first 3 months post-CDLT that didnot show significant pathologic change. The indica-tions for transplantation in the CDLT group were hep-atitis C (15 patients), 2 patients each with massivehepatic necrosis and primary biliary cirrhosis, and 1patient each with hepatitis B, Wilson’s disease, crypto-genic cirrhosis, and alpha-1 antitrypsin deficiency. Theindications for transplantation in the LDLT group werehepatitis C (13 patients), metastatic tumors (2patients), and 1 patient each with primary biliary cir-rhosis, alpha-1 antitrypsin deficiency, hepatoportalsclerosis, cryptogenic cirrhosis, hepatocellular carci-noma, and primary sclerosing cholangitis.

The LDLT group consisted of 12 males and 9females, ranging in age from 26 to 75 years (mean,57 � 10.38); the CDLT group consisted of 15 malesand 8 females, ranging in age from 42 to 71 years(mean, 54.69 � 7.02 years). There were 33 biopsiestaken from the 21 LDLT patients. Of these, 21 biopsieswere taken within 3 months of transplantation (range,4-75 days; mean, 23.85 � 12). A total of 12 biopsieshad been taken between 3 to 10 months (range, 90-300days; mean, 173.41 � 67.47 days). The 23 biopsiesfrom patients in the CDLT group were taken between 1to 72 days (mean, 23.04 � 20.84 days) (Table 1).

Of the 21 biopsies performed within 3 months inthe LDLT group, 7 had been performed intraopera-tively for repair of a bile leak (5 patients) or duringexploratory laparotomy (2 patients). The remaining

Table 1. Comparison of Biopsies Taken Within 3 Months From Patients With LDLT and CDLT

LDLT CDLT t-test

Age at transplant (yr) 57 � 10.38 54.69 � 7.02 P � nsGender (M / F) 12 / 9 15 / 8Time of biopsies (postoperative day) 23.85 � 12 23.04 � 20.84 P � nsPortal tracts / cm 6.26 � 1.62 9.08 � 1.74 P � .0001Labeling index* 4.53 � 3.72 0.82 � 0.63 P � .0005Length of biopsies (cm) 1.87 � 1.05 1.95 � 0.91 P � ns

Abbreviations: ns, not significant; M, male; F, female; LDLT, living donor liver transplantation; CDLT, cadaveric liver transplantation.*Number of positively-stained nuclei per 1,000 hepatocytes.Values expressed as mean � standard deviation.

1462 Huang et al.

biopsies were performed for abnormal liver chemistrytests to rule out acute cellular rejection or other post-transplantation pathology. Of the 23 biopsies per-formed within 3 months in the CDLT group, 2 hadbeen performed intraoperatively during an exploratorylaparotomy; the remaining biopsies were performed forelevations in liver enzymes. The histological findings inall the biopsies were minimal to mild; of the 23 biopsiesin the CDLT group, 7 showed no pathologic changes;11 showed 1 or more of the following: cholestasis, pro-liferation of bile ductules, or neutrophils around bileductules; and 4 showed 1 or more of the following: rarefoci of parenchymal necrosis, rare acidophilic bodies, ormild lobular inflammation. Of the 21 biopsies per-formed within 3 months of transplantation in theLDLT group, 6 showed no pathologic changes; 12showed 1 or more of the following: cholestasis, portaledema, proliferation of bile ductules, or neutrophilsaround bile ductules; 4 showed 1 or more of the follow-ing: rare foci of parenchymal necrosis, rare acidophilicbodies, or mild lobular inflammation; and 6 showed nopathologic changes.

The length of the biopsy specimens was comparablein the 3 groups; the average length of the biopsies in theCDLT group was 1.95 � 0.91 cm, the average lengthof biopsies taken within 3 months in the LDLT groupwas 1.87 � 1.05 cm, and the average length of biopsiestaken 3 months posttransplantation in the LDLTgroup was 1.86 � 0.74 cm. All biopsy specimens had anaverage width of 1.3 mm, having been obtained by aMenghini needle with an inner diameter of 1.3 mm.There were 9.08 � 1.74 portal tracts per cm of biopsyin the CDLT group, 6.26 � 1.62 portal tracts per cm inbiopsies taken within the first 3 months of transplanta-tion in the LDLT group, and 6.56 � 1.44 portal tractsper cm in biopsies taken between 3 and 10 monthsfollowing transplantation in the LDLT group. Thecoefficient of correlation between the length of biopsyspecimen and number of portal tracts was .94, .93, and.85 in the 3 groups, respectively (Fig. 1). These coeffi-cients show a proportionate, almost linear correlationbetween length of the biopsy and the number of portaltracts. The decrease in the number of portal tracts percm in LDLT allografts as compared to CDLT allograftswas statistically significant both within 3 months oftransplantation and after 3 months of transplantation(P � .0001 and P � .0001, respectively); the differencebetween the number of portal tracts was not statisticallysignificant between biopsies taken within 3 months oftransplantation and after 3 months of transplantationin patients who had received LDLT (P � .057) (Fig. 2).

Proliferative activity measured by MIB-1 staining

was seen predominantly in hepatocytes in both groups;bile ducts were only occasionally positive. The labelingindices in CDLT allografts and LDLT allografts withinthe first 3 months of transplantation were 0.82 � 0.63and 4.53 � 3.72, respectively. This difference was sta-

Figure 1. The coefficient of correlation between the num-ber of portal tracts and length of biopsy was .94, .93, and.85 in the CDLT group, LDLT group (biopsies takenwithin 3 months of transplantation), and LDLT group(biopsies taken after 3 months of transplantation), respec-tively. The lengths of the biopsies in the 3 groups were1.95 � .91 cm, 1.87 � 1.05 cm, and 1.86 � 0.74 cm,respectively.

1463Right Lobe Allograft Microarchitecture Change

tistically significant (P � .00056) (Fig. 3). Further-more, the labeling index in biopsies in the LDLT grouptaken within the first 3 weeks following transplantationwas 5.97 � 3.78, and that of biopsies taken 3 weeks to3 months following transplantation was 1.80 � 1.37;this difference was statistically significant (P � .0074)(Fig. 3). The difference in the labeling index in theCDLT group between biopsies taken within 3 weeks(0.82 � 0.77) and after 3 weeks of transplantation(0.81 � 0.48) was not statistically significant. Althoughthe labeling index in biopsies taken from LDLT allo-grafts after 3 weeks of transplantation was higher thanthat in CDLT allografts (1.80 � 1.37 vs. 0.82 � 0.63),this difference was not statistically significant (P �.085).

Discussion

Right lobe liver transplantation in adult recipients takesadvantage of the poorly understood but remarkableregenerative capacity of the liver to dramatically alterthe practice of liver transplantation. Imaging studieshave shown that liver volume is restored completelywithin 1–2 weeks of LDLT in both donor and recipi-ent.1–3 While there have been several studies and excel-lent reviews on the subject of right lobe transplantation,no study has addressed the pathological basis of resto-ration of liver volume.

Most of our information on liver regeneration has

been extrapolated from extensive studies in animals andcell cultures that have demonstrated multiple pathwaysof this process; the extent to which each participates orpredominates probably depends upon an interplay of

Figure 2. Histogram showing the number of portal tractsper cm in liver biopsies from patients with CDLT, and inbiopsies from patients with LDLT taken within 3 monthsand after 3 months of transplantation. The differencebetween CDLT and LDLT, both within 3 months andafter 3 months of transplantation, was statistically signif-icant. There was no statistical significance between thenumber of portal tracts in biopsies taken from patientswithin or after 3 months of LDLT (P � .057).

Figure 3. Histogram showing difference in the labelingindex of hepatocytes from patients with CDLT andLDLT. (A) The difference in labeling index in biopsiesobtained within 3 months of transplantation was statisti-cally significant (P � .00056) between patients whoreceived CDLT and those who received LDLT. (B) Thedifference in the labeling index in biopsies obtainedwithin 3 weeks and after 3 weeks of transplantation frompatients with LDLT was also statistically significant(P � .0074). (C) The difference in the labeling indexbetween biopsies from patients with CDLT and thosetaken 3 weeks after LDLT was not statistically significant(P � .085).

1464 Huang et al.

complex factors specific to the milieu under which pro-liferation occurs. These pathways include division ofmature hepatocytes, and proliferation of a facultativestem cell compartment, which may either be resident inthe liver, probably in the canals of Hering or recruitedfrom the bone marrow.5–9 Animal models that demon-strate the capacity of terminally differentiated, maturehepatocytes to proliferate include the rat partial hepa-tectomy model, the alb-uPA transgenic mouse and theFAH null mouse.10–14 Following 70% hepatectomy,the rat liver restores its original liver mass within 48hours; normally quiescent hepatocytes enter the G1phase almost immediately, the S phase roughly 12–15hours following hepatectomy, and the G2 and M phases6–8 hours thereafter. Once the mass-volume ratio isrestored, hepatocytes fall back into the G0 phase.5

When regeneration of hepatocytes is blocked by toxicagents like D-galactosamine or 2-acetylaminofluorene,regeneration takes place through the proliferation of“oval cells,” which are considered to be bipotential pro-genitor cells in the liver.15–17 Adult right lobe livertransplantation provides a unique opportunity to exam-ine liver regeneration in the human species. Althoughleft lobe allografts from living donors have been used forpediatric patients for over 15 years, this type of graftdoes not represent a reduced-sized graft that is com-pelled to proliferate. Right lobe living donor transplan-tation, on the other hand, is similar, although not iden-tical to partial hepatectomy in the rat, differing from thelatter in the amount of liver parenchyma that isremoved. The questions we sought to answer in thisstudy were: What is the histopathologic correlate ofvolume restoration following right lobe transplantationseen with imaging studies, and in particular, what is thepredominant proliferative compartment of the liverresponsible for this process? If volume restorationoccurs by proliferation of mature hepatocytes, do portaltracts proliferate in concert? If they do not, is there arelative decrease in the number of portal tracts? Studymaterial is obviously limited to diagnostic biopsiesobtained from recipients and suffers from the presenceof posttransplantation modifiers like preservationinjury, viral infection, acute cellular rejection, and drughepatotoxicity. To eliminate the effects of these modi-fiers as much as possible, we selected cases in whichhistological changes were minimal or not present at all.

This study demonstrates a statistically significantincrease in the labeling index of hepatocytes with theproliferation marker MIB-1 in adult patients whoreceive right lobe allografts when compared to cadavericwhole liver allografts, thus confirming the hypothesisthat volume restoration in humans following LDLT

occurs by proliferation of hepatocytes. We have alsoshown that most of this restoration occurs within thefirst 3 weeks following LDLT. This is evidenced by thefact that the difference in labeling indices is statisticallysignificant between biopsies taken within 3 weeks ofLDLT and those taken after 3 weeks of LDLT.Although the labeling index in biopsies taken 3 weeksafter LDLT is higher than in biopsies of patients withCDLT, this difference looses its statistical significanceafter 3 weeks of transplantation. This study, therefore,provides the pathological correlate of the almost com-plete restoration of liver volume that is seen radiologi-cally within 3 weeks of LDLT.

This study also demonstrates a statistically signifi-cant decrease in the number of portal tracts in right lobeallografts compared to whole liver allografts. The rightlobe allograft, therefore, appears to regain standard livervolume in the adult recipient through proliferation ofhepatocytes, thus increasing the distance between por-tal tracts so that the fully restored allograft contains lessportal tracts than that present in a nonreduced graft.The liver displays remarkable metabolic heterogeneityalong the portal-central axis and along the interportalsepta, so that opposite metabolic pathways such as glu-coneogenesis and glycolysis are carried out simulta-neously by hepatocytes in periportal and perivenularregions, respectively, a biologic phenomenon some-times referred to as “collective intelligence” of an “altru-istic” organ.18–20 To perform this complex task, theliver depends on the integrity of its microarchitecture, ahighly complex organization of functionally heteroge-nous anatomical and physiological components. Thequestion, therefore, arises whether the altered microar-chitecture in volume-restored right lobe allograftsaffects liver function to any significant degree. Clinicalexperience has shown normalization of liver function testswithin the first week of transplantation in both donor andrecipient. No significant differences are observed in levelsof alanine aminotransferase and aspartate aminotransfer-ase or prothrombin time between donors, recipients ofpartial grafts, and recipients of cadaveric grafts. Bilirubinlevels normalize within 1 week in both donors and recipi-ents, and levels of factor VII are significantly differentbetween recipients of cadaveric grafts vs. those of partialgrafts and donors during the first 3 days posttransplanta-tion, but normalize thereafter.3 These observations indi-cate that despite the microarchitectural changes found inthis study, liver function is restored to normal at least withrespect to the above parameters; this suggests an adjust-ment of the organ to changes in microarchitecture, and isperhaps another example of hepatic altruism. It is not clearwhether hepatocytic proliferation and altered microarchi-

1465Right Lobe Allograft Microarchitecture Change

tecture have any effect on the metabolism of immunosup-pressive drugs, and if this accounts for the observed higherserum levels of these agents in the early postoperativeperiod in adult patients who have received right lobesallografts.21

Two previous studies have examined the histologicalfindings occurring in volume-restored allografts follow-ing right lobe LDLT. In 1 study, 18% of 58 patientswith right lobe LDLT showed features of outflowobstruction in the form of sinusoidal dilatation, centri-lobular spotty necrosis, and central vein fibrosis; thesefindings were not seen in any of the 123 patients whohad received a cadaveric whole liver during the sameperiod. As the authors suggest, this may indicate aninability of the limited venous system of the right lobeto adequately drain the entire regenerated liver. Overtime, these changes might conceivably put the recipientat increased risk of developing fibrosis and significantgraft damage.22 Similarly, histological findings sugges-tive of bile duct obstruction are most common inpatients who receive right lobe LDLT; many of thesepatients do not have mechanical obstruction to the bileduct. The biopsy findings are those of centrilobularballooning and cholestasis, bile ductular proliferation,and cholate injury.22–24 The question arises as towhether these changes are an indication of inadequatebiliary drainage of the hepatic parenchyma due to adisturbance of the fine microarchitectural pattern ofintralobular biliary channels.25 It is perhaps relevantthat most recipients experience hyperbilirubinemia inthe early posttransplant period, even when the graft sizerepresents 60% of expected liver volume.3,26 Long-termstudies will eventually answer these questions, all themore vital in the context of the donor, in whom prolif-eration may or not may be entirely similar to that of theimmunosuppressed host. Some studies have suggestedthat regeneration is slower and peak volumes lower indonors when compared to recipients.27

Last, this study confirms previously published reportsthat liver regeneration occurs in the immediate posttrans-plantation period; there was a statistically significant dif-ference in the labeling index of hepatocytes within andafter 3 weeks of receiving a reduced allograft.

In conclusion, we have shown that restoration ofliver volume and mass in reduced right lobe allograftsoccurs by proliferation of mature differentiated hepato-cytes within the first 3 weeks of transplantation. This isaccompanied by a relative decrease in the number ofportal tracts. The fact that there is restoration of normalliver function within weeks of transplantation suggestsremarkable adjustment of the liver to the new microar-chitecture; the long-term consequences remain to be

seen. This is an important issue, as the practice of rightlobe LDLT continues to provide a useful therapeuticmodality, creating not just a sizeable group of recipientswith right lobe allografts, but also a group of healthyindividuals with reconstituted livers.

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