
 despite the marked advances in the perioperative management of the liver transplant recipient , an assessment of clinically significant graft injury following preservation and reperfusion remains difficult .
the lack of a sensitive clinical marker of acute liver injury has a profound impact on clinical practice and the success of translational research in liver transplantation .
such a clinical marker could aid the management of graft dysfunction in early identification of recipients who will require retransplantation .
currently , posttransplant peak aspartate aminotransferase ( ast ) is a widely accepted clinical marker for graft damage in liver transplant practice [ 26 ] .
in fact , the united network for organ sharing ( unos ) suggests relisting criteria for the recipients with primary graft dysfunction ( pnf ) on the basis of the post - transplant peak ast .
ast is an enzyme that is involved in amino acid metabolism , primarily existing in hepatocytes . during transplantation graft hepatocytes
are inevitably injured , and intracellular enzymes are subsequently released into the systemic circulation of the recipient .
we theorized that the recipient ast serum concentration is a function of the total amount of ast released by the graft liver diluted by the total circulating blood volume at the time of blood sampling .
therefore , the ast value could be misleading or inaccurate , depending on the size of the graft ( total mass of injured hepatocytes ) and the volume of blood in the recipient 's circulation .
we have previously reported on the use of the ratio of donor to recipient body surface area ( bsai ) to predict donor - recipient graft size mismatch [ 8 , 9 ] .
we showed that size mismatch has a bidirectional impact on graft survival with a progressive increase in the risk of graft failure towards both ends of the size - mismatch spectrum , small - for - size to large - for - size 5 by generalized additive model .
bsai has an important value in deceased liver transplant to quickly and reliably predict size - mismatch - related comorbidities and graft outcome . in this study
, we hypothesized that serum ast when adjusted by the ratio of the donor - to - recipient body surface area ( asti ) could more accurately approximate the true mass of injured hepatocytes than the uncorrected or absolute peak ast , subsequently providing a more precise assessment of graft fate . in order to test this hypothesis
, we conducted a study to investigate the sensitivity and specificity of asti versus absolute peak ast to predict pnf and graft survival in a large cohort of postliver transplant patients .
after institutional review board approval , primary retrospective data collection was from patient records who underwent whole orthotopic liver transplantation ( lt ) from january 2002 to march 2008 at our institution ( jackson memorial hospital , university of miami , leonard miller school of medicine , miami , fl , usa ) .
we were interested in the effect of size - matched peak ast ( asti ) on postoperative outcomes .
therefore , among all transplant recipients , we excluded those who underwent split or partial lt as well as those who underwent simultaneous other organ transplantation , such as liver - kidney , liver - heart , liver - intestine , or multivisceral transplantation or live donor lt .
body surface area index ( bsai )  to investigate donor - recipient size mismatch on postoperative primary graft dysfunction [ 8 , 9 ] .
the bsai was calculated by the following equation : 
 ( 1)bsa = weight  ( kg)0.425height  ( cm)0.7250.007184bsai = donor  bsarecipient  bsa . 

size - adjusted peak ast ( asti ) was calculated by dividing peak ast by bsai .
peak ast was defined as maximum ast within 7days after lt .  
 statistical analysis .
primary nonfunction ( pnf ) of liver graft is the most detrimental condition after transplantation .
unos suggests the listing criteria for recipients with pnf as an ast 3,000 and a pt - inr 2.5 or acidosis ph 7.30 ( arterial ) , ph 7.25 ( venous ) , and/or lactate 4  mmol / l or anhepatic candidate within 7 days after implantation of a graft .
of these criteria , the combination of ast and pt - inr was used for comparative purposes in this study .
scatter plotting was used to show the statistical association between ast and asti with subsequent development of pnf .
the area under the receiver - operating - characteristic curve ( auc ) was used to evaluate diagnostic accuracy of asti relative to that of conventional ast .
the predictive value of current unos criteria for pnf ( by combination of ast and pt - inr ) was assessed by sensitivity and specificity in our study cohort .
the logistic regression model was used to describe the association between seven study groups differentiated by ranges of asti and the incidence of pnf .
all recipient and donor variables were included in the multivariable model . to assess the independence of asti effect on pnf , a backward conditional elimination procedure was then undertaken using the donor and recipient demographic factors .
cox proportional - hazards models were used to examine the association between seven study groups differentiated by ranges of asti and graft survival ; data were censored at the time of the last visit or patient death .
one - year graft survival was used to assess the short- and mid - term effect of asti .
covariates were analyzed by using a backward conditional method with the donor and recipient demographic factors .
kaplan - meier survival analysis with generalized wilcoxon analysis was used to assess the difference in graft survival between asti 3,500 and asti < 3,500 .
, college station , tx ) were used for statistical analysis and all reported p values are two - sided , and p values of less than 0.05 were considered to indicate statistical significance .
a total of 930 whole lt procedures performed from january 2002 to march 2008 were reviewed in this study .
717 out of 930 consecutive whole olt performed from january 2002 to march 2008 were included in this study .
a total of 213 patients were ultimately excluded from the analysis for the following reasons : live donor lt ( 1 case ) , split lt ( 24 cases ) , auxiliary partial lt ( apolt , 6 cases ) , fulminant hepatic failure ( 14 cases ) , and simultaneous other organ transplants ( 55 cases ) as well as missing data ( 113 cases ) . 

the base - line characteristics of the recipients and donors of lt are summarized in table 1 .
figure 1 shows a scatter plot of the relationship between peak ast and size - adjusted ast ( asti ) for cases with or without subsequent development of pnf .
diagonal blue dot line shows 1  :  1 correlation between ast and asti .
cases above this reference line had a large - for - size graft and below the line a small - for - size graft .
iu / l , which is the current criterion for relisting as pnf suggested by unos . 

prediction of pnf by ast and asti . a receiver - operating - characteristic ( roc ) curve for ast and adjusted ast ( asti ) at risk for pnf
roc curves show the relationship between true positive and false positive rates for a test across various threshold values used to diagnose a condition .
the area under the curve ( c statistic ) for the roc shown in asti is 0.930 .
unos criteria of pnf had a sensitivity of 75% and specificity of 97.7% in our study cohort . the combination of asti 3,500 
iu / l and pt - inr 2.3 had the best predictive value , with a sensitivity of 87.5% and a specificity of 98.0% , which was better than that obtained with unos criteria . 

improvement of prediction for pnf was further assessed by a case - by - case comparison of results between conventional unos criteria and asti criteria ( table 2 ) .
seven cases were identified as the cases which had different results between conventional unos criteria and new asti criteria .
five cases had better results with new asti criteria and two cases had better results with conventional unos criteria . of three cases with the diagnosis of small - for - size donor , one case had a better result with asti due to improvement by size adjustment .
of four cases with the diagnosis of large - for - size donors , three cases had better result with asti for the same reason . 

predictive values of different asti cutoffs for the primary nonfunction of the graft were analyzed with a logistic regression model ( figure 3(a ) ) .
a logistic regression model showed that asti has significant impact on pnf ( hazard ratio 1.0003 ( 95% ci : 1.00031.0007 ) , p = 0.00001 ) . if asti was greater than 2,000 
iu / l , there was an exponential increase of hazard risk ratio for pnf along with increased asti .  

predictive value of asti for one - year graft survival in the cox proportional hazard model .
predictive value of different asti cutoffs for one - year graft survival was analyzed with cox proportional hazard model ( figure 3(b ) ) .
a cox proportional hazard model showed that asti has significant impact on graft survival ( hazard ratio 1.0002 ( 95% ci : 1.00011.0003 , p = 0.00012 ) . if asti is greater than 3,500 
iu / l , there is an exponential increase of hazard risk ratio for pnf along with increased asti .  

comparison of one - year graft survival in patients with asti 3,500  iu / l and asti < 3,500  iu / l .
because asti had significant impact on one - year graft survival , we divided our study cohort into two groups : asti 3,500 
then graft survival was compared by kaplan - meier survival analysis with generalized wilcoxon analysis .
kaplan - meier survival analysis showed the probability of the primary graft outcome among patients who had a peak - adjusted ast ( asti ) of greater than 3,500 
iu / l along with those who had an asti of less than 3,500  iu / l ( figure 4 ) .
the graft survival at 1 year was 73.8% in the asti > 3,500  iu / l group and 83.7% in the asti < 3,500  iu / l group .
there was a significant reduction in graft survival in asti > 3,500  iu / l group ( p = 0.004 ) .
despite the significant advances in the management of the liver transplant ( lt ) recipient , the quantitative assessment of graft damage remains uncertain .
acute injury and inflammation of transplanted organs during the immediate postoperative period may be linked to early organ dysfunction resulting in higher graft failure rates and rejection in the recipient .
therefore , development of appropriate clinical markers to identify organ injury in the early postoperative period will have a profound impact on patient outcomes as well as on the success of clinical and translational research [ 11 , 12 ] .
such clinical markers of liver damage can be of assistance in identifying the mechanisms of liver inflammation and injury and predisposing factors of donor organ injury , making it possible to implement injury - specific treatment strategies to promote organ resuscitation . in response to the transplant community 's urgent need for a useful clinical marker of injury , ongoing nih clinical trials in organ transplantation
have attempted to investigate posttransplant genomic expression patterns , which may correlate with a high probability of graft dysfunction or failure .
currently , in lt practice posttransplant peak ast is the most widely accepted clinical markers of graft damage .
ast is an enzyme that is involved in amino acid metabolism , primarily existing in liver as well as heart , skeletal muscles , kidney , and brain .
when hepatic parenchymal cells are injured , ast is released into the systemic circulation , causing an elevation of serum ast . however , the serum ast level depends on the mass of the donor liver graft ( the degree and extent of injured and dying hepatocytes ) and on the recipient circulatory blood volume . the working hypothesis that guided
this study is that the peak ast  corrected  by the ratio of donor - to - recipient body surface area could be determined to be more accurately associated with the degree of graft injury , thus better predicting graft outcome in lt .
indeed , the results of this study prove that the size - adjusted peak ast ( asti ) has higher sensitivity and specificity to predict pnf compared to size - unadjusted ast .
iu / l and either ( a ) inr 2.5 or arterial ph 7.30 or venous ph 7.25 and/or lactate 4mmol / l , ( b ) anhepatic patient within 7 days after transplantation . in our study cohort , when we applied unos criteria , we found a relatively low sensitivity of 75.0% and specificity of 97.7% .
this relatively high false positive result with conventional unos criteria may be due to the fact that some cases of pnf occurred in small - for - size donors as shown in figure 1 , where ast is more likely to underestimate the severity of graft damage based on the reasoning previously described .
also , we found that the severity of graft damage in large - for - size donors can be overestimated by size - unadjusted ast .
in fact , one case was underestimated and three cases were overestimated by conventional criteria and this  error  was corrected by asti criteria as shown in table 2 . when we used size - adjusted ast ( asti ) , the combination of size - adjusted asti and pt - inr predicted pnf more accurately , and the sensitivity increased to 87.5% with a specificity of 98.0% at cutoff of asti 3,500  iu / l and pt - inr 2.3 .
in addition , asti correlated well with the incidence of pnf and short - term graft survival .
increases in asti were significantly associated with increasing incidence of pnf . also asti was highly correlated with the incidence of 1-year graft failure , if asti exceeded 3,500  iu / l
. a more sensitive prediction of pnf with asti will enable clinicians to more accurately identify the recipient who requires retransplantation , perhaps , at an earlier stage in the postoperative period , resulting in better patient outcome .
one - year graft survival ( shown in figure 4 ) showed that asti > 3,500  iu / l group was associated with a steep decrease in graft survival in the early postoperative period compared to asti < 3,500  iu / l group .
these findings suggest that in lt markers of postoperative graft injury should be interpreted with caution by taking into account graft size mismatches .
bsai appears to be a powerful tool to detect donor - recipient size mismatch in cadaveric lt but awaits further validation .
small - for - size or large - for - size grafts not only have been attributed to decreased graft survival , increased additional graft usage ( retransplantation ) , and increased incidence of other complications but also have made an assessment of posttransplant graft injury difficult .
this study has demonstrated that size mismatch may have an even greater negative impact on graft outcome in the presence of other donor risk factors , such as prolonged cold ischemia .
furthermore , the lack of a suitable clinical measure to reliably predict size mismatch has probably hindered our ability to judge its clinical importance in cadaveric lt .
bsai provides a simple , reproducible , and sensitive way of detecting size mismatch in cadaveric lt .
second , fluid excess ( ascites and edema ) is universal in end - stage liver disease .
fluid excess causes weight - to - height parameters such as percentage ideal body weight , bmi , and bsa to be underestimated , and the bsa of the recipient may not accurately reflect the liver volume in these situations .
alternative ways to more accurately detect size disparity may be ( i ) measuring the donor graft weight at back table or ( ii ) using the recipient 's dry weight instead of recipient bsa .
however , we believe that asti is a simple , reproducible , and sensitive predictor of graft outcome associated with size mismatch .
the liver has the excellent regenerative capacity even in the face of significant loss of hepatocyte mass .
this has been demonstrated after liver resection or traumatic hepatic injury [ 14 , 15 ] .
once mass ( volume ) or functional compensation starts , bsai may no longer accurately reflect the size mismatch between donor and recipient . in experiments with rodents , regeneration of liver mass occurred by 3 days after hepatectomy and restoration is complete by 57 days .
recent clinical observations showed that recipients of partial grafts have a rapid proliferation of liver mass , with a majority reaching a calculated standard liver volume by one month [ 17 , 18 ] .
although several factors have been proposed to explain the delay in the regeneration process , such as small - for - size donor , severity of ischemic injury , immunosuppressive medications , presence of steatosis , and older age , for these reasons the use of bsai - adjusted liver enzymes as more sensitive and specific markers of liver injury should be limited to the immediate postoperative period .
lastly , although asti seems to be a useful index to predict outcome in adult olt , it remains unclear whether asti is also useful in pediatric olt .
since slv calculated with bsa can be applied to pediatric populations , asti should also be applied to pediatric patients and should provide useful information for preoperative estimation of liver grafts regardless of age . however , predicting outcome by bsai for pediatric population warrants further investigation .
we conclude that the asti appears to be a sensitive predictor of postoperative liver graft injury in the early postoperative period . despite some shortcomings
, we believe our analysis shows that the asti may provide significantly better prediction of size mismatch - related graft dysfunction in lt .
finally , we believe that asti should be considered in the early identification of graft dysfunction or pnf and should be validated in a prospective study to see whether it accurately and consistently predicts pnf or graft function and reduces posttransplant mortality .
 
 background . despite the marked advances in the perioperative management of the liver transplant recipient , 
 an assessment of clinically significant graft injury following preservation and reperfusion remains difficult . in this study , we hypothesized that size - adjusted ast could better approximate real ast values and consequently provide a better reflection of the extent of graft damage , with better sensitivity and specificity than current criteria . 
 methods . 
 we reviewed data on 930 orthotopic liver transplant recipients . 
 size - adjusted ast ( asti ) was calculated by dividing peak ast by our previously reported index for donor - recipient size mismatch , the bsai . 
 the predictive value of asti of primary nonfunction ( pnf ) and graft survival was assessed by receiver operating characteristic curve , logistic regression , kaplan - meier survival , and cox proportional hazard model . results . 
 size - adjusted peak ast ( asti ) was significantly associated with subsequent occurrence of pnf and graft failure . in our study cohort , 
 the prediction of pnf by the combination of asti and pt - inr had a higher sensitivity and specificity compared to current unos criteria . 
 conclusions . 
 we conclude that size - adjusted ast ( asti ) is a simple , reproducible , and sensitive marker of clinically significant graft damage . 
1. Introduction
2. Methods
3. Results
4. Discussion