Sunday Poster Sessions,
October 29, 2006
Immunosuppression, Outcomes, Complications
576. MULTICENTER RANDOMIZED HEPATITIS C (HCV) - THREE TRIAL POST LIVER TRANSPLANTATION (OLT): TWO-YEAR INTERIM REPORT. C. G.
Fasola; T. G. Heffron; L.
Sher; D. Douglas; R. Brown; J. Ham; L. Teperman; M. Hanaway; D. Eckhoff; K.
Washburn; M. Millis; J. Roberts; M. Charlton; P. Baliga; T. Pruett; B. Koneru;
E. Pomfret; M. Abecassis; G. B. Klintmalm.
Aims:
To assess the efficacy and safety of steroid (Pred)-free
immunosuppression (IS) with daclizumab (DAC), tacrolimus (TAC) and
mycophenolate mofetil (MMF) to minimize acute cellular rejection (ACR), HCV
recurrence (HCVR) and adverse events post OLT.
Methods:
Ongoing open label, prospective, multicenter study involving
312 adult HCV-OLT recipients randomized pre-OLT (1:1:2) to three IS regimens
(see Results). Laboratory data and liver histology (local pathologists) done
when clinically indicated and, by protocol, at 90, 365 and 730 days. ACR graded
by Banff classification. HCVR staged by according to Batts and Ludwig. Primary
endpoints: clinically significant ACR (Grade 2 + RAI 4) and/or HCVR (Stage 2 by
day 365 and/or stage 3 by day 730 or Grade 3 at any time). Significant
statistics: p ≤ 0.05* (Fishers exact test).
Results:
For this abstract, 166 patients were evaluable for 2-year
endpoints: Arm 1 (n=42): TAC+Pred; Arm 2 (n=42): TAC+Pred+MMF; Arm 3 (n=82):
3-dose DAC+TAC+MMF (steroid-free). Available data: ACR: 165 (99%) and, HCVR:
155 (93%). Data reported for Arms 1, 2, 3, respectively. Rejection-free
incidences: 85%, 89% and 91%; mild ACR: 3 (33%), 4 (50%) and 10 (63%); moderate
ACR: 5 (56%), 1 (13%) and 6 (37%); severe ACR: 1 (11%), 3 (38%) and 0 (0%)
patients (p < 0.05: 2 vs. 3*). HCV recurrence-free incidences: 11%, 8%, and
20%; moderate HCVR: 2 (40%), 6 (46%) and 8 (50%); severe HCVR: 1 (20%), 2 (15%)
and 2 (12%). More aggressive HCVR (greater than 1 stage increase between days
90 and 365 biopsies) progression was observed in Arm 1 (9, 32%) vs. 2 (6, 25%)
and 3 (15, 23%). Cox proportional hazards model showed ACR is an independent
risk factor for HCVR (HR 8.22, p=0.003). Quantitative HCV-RNA levels similar in
all groups as were the incidences of post-transplant diabetes mellitus (PTDM),
malignancies, infections, hypertension (HTN) and hyperlipidemia. Graft
survival: 71%, 77% and 76% (NS). Patient survival: 75%, 77% and 78% (NS).
Similar death causes: HCVR (4, 1, 3), respiratory (0, 2, 5), malignancy (1, 4,
1), sepsis (2, 1, 3); others (3, 1, 4).
Conclusions:
This 2-year interim report suggests that steroid-free IS with
DAC/TAC/ MMF is safe and effective, with low incidences of ACR and severe ACR.
ACR appears to be a presumptive factor in HCVR. At present doses, steroids seem
to be subordinate compared to other IS medications or comorbidities as a risk
factor for PTDM or HTN. Updated 2-year data will be presented at the time of
the meeting.
577. Rates of Special Case MELD Exception Awards and Liver Transplant Waiting List Death Vary by UNOS Region.
C.
K. Argo; C. L. Berg; G. J. Stukenborg; P. G. Northup.
Background/Aims:
Introduction of MELD exceptions raised concern about possible
“gaming” of the liver allocation system. Request and approval rates for
exceptions for reasons such as refractory ascites, termed “special case”
exceptions (SCE), vary widely by region. We aimed to confirm regional
differences in rates of SCE requests and approvals and to examine correlations
of rates of SCE and waiting list deaths (WLD).
Methods:
81434 patients were included from the UNOS database of adult
OLT candidates during the MELD era (run date 4/24/06). Patients who underwent
LDLT, repeat or multiorgan transplant, or who received an HCC-exception were
excluded. Rates of SCE requests and approvals and WLD rates were compared using
ratios standardized by regional adult population. Organ shortage by region was
estimated using the ratio of the number of waiting list patients with MELD >
15 at run date divided by offered organs in 2005. Pearson correlation
coefficients (PCC) were calculated to quantify degrees of association between
variables across regions.
Results:
There was a wide range of regional variation in SCE request and
approval rates, WLD rates, and standardized organ shortage ratios (Table). The
highest per capita rate of WLD was 64.3/million adults with standardized
mortality ratio (SMR) of 2.26 (region 9) and lowest was 9.18/million with SMR
of 0.32 (region 6). Regions with higher rates of SCE approvals also had higher
rates of WLD (PCC=0.89, p=0.002). The severity of organ shortage varied with
WLD in a similar pattern (PCC=0.84, p=0.012), but there was much less
association between SCE approval rates and organ shortage (PCC=0.6, p=0.05) and
between SCE approval rates and mean lab-based MELD at transplant, another
indicator of organ shortage (PCC=0.38, p=0.25).
Conclusions:
There is clear regional variation in patterns of requesting
and approval of special case MELD exceptions for liver transplant. The
differences in the degree of correlation between WLD rates, SCE approval rates,
and organ shortage measures, however, suggest that observed rates of SCE
approval are not reliant solely on degree of regional organ shortage but also
vary due to basic regional differences in philosophy concerning awarding SCE
for individual patients. These regional differences likely represent an area of
inconsistency in the application of the MELD allocation system that may affect
WLD rates.
579. Effect of gender mismatch on acute cellular rejection and graft failure in liver transplant recipients.
M.
K. Oh; S. Colquhoun; F. F. Poordad; T. T. Tran.
Background:
Previous studies have shown that gender mismatch between
liver transplant donor and recipient, in particular female donor to male
recipient, may be associated with decreased graft and patient survival. While
the mechanism for this is unclear, an increase in acute cellular rejection
(ACR) due to immunologic differences in gender could play a role.
Aims:
Determine the effect of donor and recipient gender on
incidence of acute biopsy proven rejection as well as graft failure.
Methods:
Retrospective analysis was done on deceased donor liver
transplants performed at Cedars-Sinai Medical Center from 2000-2005. Recipient
age, gender, race, type of liver disease, immunosuppression, peak
aminotransferases, and liver biopsy data was collected, along with donor age
and gender. Graft failure was defined as patient death or retransplantation.
Four donor/recipient gender pairs were evaluated: female to
female (F/F), male to female (M/F), female to male (F/M), and male to male
recipient (M/M). ACR was also evaluated in three specific gender subsets:
gender matched vs. gender mismatched; female recipient vs. male recipient; and
female donor vs. male donor, using Fischer’s exact test and logistic
regression.
Results:
A total of 99 deceased donor liver transplants were analyzed.
Sample sizes of donor/recipient pairs yielded: F/F=17, M/F= 18, F/M= 26, M/M=
38. Overall incidence of ACR at 1 year was 37%. Recipient age, race,
aminotransferases, and donor age did not differ amongst the groups. Incidence
of ACR was similar across all four donor/recipient combinations, p=NS: F/F
(47%), M/F (39%), F/M (35%), M/M (34%). ACR occurred in 21 of 55 gender matched
pairs (37%) and 16 of 44 gender mismatched pairs (36%), p=NS. In the donor
gender subset, ACR occurred in 17 of 43 transplants with a female donor (40%)
and 20 of 56 transplants with a male donor (36%), p=NS. In the recipient gender
subset, ACR occurred in 15 of 35 transplants with female recipients (43%) and
22 of 64 transplants with male recipients (34%), p=NS. Multivariable analysis
of gender, race, recipient and donor age, aminotransferases, etiology of liver
disease (HCV, PBC, PSC, AIH) failed to reveal gender mismatch as an independent
predictor of ACR. Overall incidence of graft failure at 1 year was 15%,
occurring in 6 of 55 gender matched pairs (11%) and 9 of 44 gender mismatched
pairs (20%), p= NS.
Conclusion:
Despite previous reports showing decreased graft and patient
survival in female donor to male recipient deceased donor liver transplants,
ACR was not observed more frequently in gender mismatched donor/recipient
pairs, suggesting another possible mechanism of graft injury.
580. Effects on survival of listing vs not listing patients with low MELD scores.
J.
Rai; M. S. Campbell; E. Kozin; J. Markmann; K. Olthoff; A. Shaked; K. Reddy.
Introduction:
The survival benefit of listing cirrhotic patients with low
MELD for orthotopic liver transplantation (OLT) is not well known.
Aim:
Among patients with low MELD scores, we sought to compare
survival between patients who were listed and not listed for OLT.
Methods:
We identified 1,102 patients evaluated for OLT at our
institution (2002-2004). After excluding patients with hepatocellular
carcinoma, active alcohol and substance abuse, medical contraindications to OLT,
and living donor candidates, we identified 240 patients with MELD scores ≤
12. 118 subjects were listed and 122 were not listed for OLT. We obtained
clinical data (age, race, gender, etiology, diabetes, coronary artery disease,
hypertension, hepatic decompensations, presence of TIPS, and history of drug
and alcohol use) from our comprehensive, prospectively maintained transplant
database. Mortality data were obtained from the social security death index. We
compared survival between the two cohorts using Kaplan-Meier survival analysis
and Cox proportional hazard modeling.
Results:
Among the 122 patients not listed, 69 (56%) were considered
too early for listing, and 51 (42%) did not complete listing evaluation. Listed
patients tended to have a higher MELD score than those not listed (10.1 +/- 1.5
vs. 9.3 +/- 1.9, p=0.001). Furthermore, listed patients more often had ascites
(93 (78%) vs. 66 (54%), p=<0.001) and were more often white (109 (92%) vs.
99 (81%), p=0.01) and male (83 (70%) vs. 64(52%), p=.005). The average
follow-up time was 22.6 +/- 11.3 months and was similar in both cohorts
(p=0.45). Listing for OLT was associated with a 0.69 (0.36-1.35, p=0.28)
hazards ratio for mortality. Adjusting for MELD, ascites, and hepatic
encephalopathy, the hazards ratio for mortality in those listed for OLT was
0.45 (0.23-0.90, p=0.026), which was statistically significant. Restricting
analysis of not listed patients to only those who were considered too early for
liver transplant (well controlled or no hepatic decompensations) did not
substantially alter this point estimate. After progressively restricting MELD
threshold for study inclusion from 12 to 8, we could not identify a minimal
MELD threshold at which a survival difference between listed and not listed patients
was lost.
Conclusion:
a) listing patients with low MELD is
associated with a statistically significant survival advantage.
b) we could not identify a minimum MELD
to achieve a survival benefit
c) We speculate that the survival
advantage results from additional close follow-up provided to listed patients.
581. Impact of MELD Allocation on Post-OLT Renal Failure: Analysis of the UNOS Database.
D.
Batty; N. R. Krieger; Y. Yu; S. Ray.
Introduction:
For patients receiving non-renal solid organ transplants,
post-transplant renal failure rates are highest in OLT (OLT) recipients. The
impact of the MELD allocation system in 2002 has had an unknown impact on this
rate of renal failure. With renal function included as one of the three
variables in the MELD formula, implementation of this allocation policy could
have had the inadvertent impact of greater incidence of post-OLT renal failure.
An analysis of the UNOS database for OLT recipients was performed to evaluate
this possibility.
Methods:
We used the Standard Transplant Analysis and Research (STAR)
data from the United Network for Organ Sharing (UNOS) to examine the incidence
of renal failure (RF) observed in patients who had liver transplant (OLT)
during 1998 - 2006. All patients in the database with OLT between 1/1/1998 and
6/30/2006 were selected. Patients with an OLT before 2/28/2002 were grouped as
the pre-MELD cohort, and the remaining patients were grouped as post-MELD
cohort. Patients with renal failure were identified as someone who was listed
or received a kidney transplant. A minimum follow-up period of 18 months after
the liver transplant was required for patients without observed renal failure
to be included in the analysis. Rates of renal failure and LKTx were computed
at 6, 12, and 18 months post-OLT for the pre-MELD and post-MELD cohorts, and
compared using Chi-square test.
Results:
A total of 22,796 patients with a mean age of 45.9 (SD=17)
years were identified for the analysis, of whom 14,280 (63%) were male. Of the total,
14,903 (65%) patients were classified into the pre-MELD cohort and 7,893 (35%)
patients to the post-MELD cohort. The 6-month, 12-month, and 18-month post-OLT
incidence of observed renal failure in the pre-MELD cohort were 3.4%, 3.7%,
3.9% respectively. The corresponding 6-month, 12-month, 18-month incidence
rates in the post-MELD cohort were 12.8%, 13.6%, 14.0% respectively
(p<0.0001 for all 3 differences). The incidence of dual LKTx was 450 (3%)
vs. 949 (12%) in the post-MELD cohort (p<0.0001).
Summary:
An analysis of the UNOS database for the effect of the MELD
allocation policy change for OLT revealed a dramatic increase in the number of
patients with renal failure post- OLT. This was primarily driven by a dramatic
increase in the number of concomitant LKTx performed. This could result in
increased competition between patients awaiting OLT and KTx for a fixed number
of kidneys. This would likely result in a significant increase in waiting time
for patients listed for KTx. Strategies to address renal failure in OLT are
needed to reduce the incidence of post-OLT renal failure.
582. Randomized Prospective Study Suggesting Worse Outcomes For Complete Steroid Avoidance in Liver Transplantation.
A.
Magar ; S. J. Pelletier; M. J. Englesbe; T. H. Welling; W. N. Al-Holou; R. J.
Fontana; J. D. Punch.
Introduction:
Steroids are a mainstay in liver transplantation (OLT) for
induction and maintenance immunosuppression but are associated with significant
adverse effects.
Aims:
While prior studies have successfully limited the use of
steroids, whether complete steroid avoidance will improve outcomes remains
unclear.
Methods:
Patients undergoing OLT between 6/02 and 4/05 were entered
into a prospective, randomized trial of complete steroid avoidance and followed
until 6/06. Recipients received either standard therapy (tacrolimus,
mycophenolate, steroid induction/maintenance; N=50) or complete steroid
avoidance (standard therapy without steroid induction/maintenance; N=50).
Clinically suspected rejection was confirmed by biopsy and treated with pulse
steroids. Donor and recipient characteristics and outcomes were compared on an
intention to treat basis.
Results:
The mean follow up of all recipients was 774±40 days. Fifteen
(23%) recipients randomized to no steroids ultimately did receive steroids for
a clinical indication. Recipient characteristics (age, race, gender, MELD
score, diagnosis, and comorbidities) and donor characteristics (age, race,
gender, and ischemic times) were similar between groups. No difference was
observed in the incidence of diabetes or hypertension prior to or after OLT
although the steroid group required more antihypertensives at 1 year (0.86±0.15
vs. 0.51±0.10 meds per patient, p=0.05). While the incidence of acute and
chronic renal failure was similar, those not receiving steroids had a higher
serum creatinine at 6 months (1.60±0.14 vs. 1.24±0.11 mg/dl, p=0.05) and
required a longer time on hemodialysis (257±85 vs. 50±31 days, p=0.03) There
was no difference in the incidence of acute or chronic rejection. The incidence
of recurrent HCV was similar between the steroid avoidance group and standard
therapy (56% vs. 43%, p=0.33) but increased graft fibrosis at 1 year was
present for those not receiving steroids (3.3±0.4 vs. 1.8±0.4 Ishak score,
p=0.02). While early (1 and 2 year) survival rates were similar, comparison of
3 year patient and graft survival rates demonstrated a trend toward decrease
survival in the steroid avoidance group (62.5% vs. 81.6%, p=0.13; 60.6% vs.
81.6%, p=0.07; respectively).
Conclusion:
Complete steroid avoidance provides liver transplant
recipients with minimal benefit, while demonstrating a concerning trend toward
increased graft loss, recipient death, and accelerated allograft fibrosis
related to recurrent HCV. These data suggest that at least a short course of
steroids should be used following OLT.
583. MYCOPHENOLATE MOFETYL (MMF) MONOTHERAPY IS AN ATTRACTIVE STRATEGY IN LIVER TRANSPLANT RECIPIENTS WITH SEVERE SIDE EFFECTS OF CALCINEURIN INHIBITORS (CNI).
S.
Dharancy; C. Sammartino; A. Hulin; N. Declerck; A. Iannelli ; P. Mathurin; E.
Boleslawski; J. Gugenheim; F. Pruvot.
Introduction:
CNI are associated with severe side-effects such as chronic
renal failure (CRF). Most of transplant centers decrease CNI doses (sparing
strategy) in pts with CNI-induced toxicity (CIT). However it is not sufficient
to improve renal function in all pts, therefore, CNI withdrawal and MMF
monotherapy has been evaluated in small cohort-size studies which reported 0 to
60% risk of acute rejection.
Aim:
to evaluate the results of MMF monotherapy in pts who
presented severe CIT.
Methods:
We identified all pts treated with MMF monotherapy for severe
CIT. 3 periods were considered: 1) period with usual dose of CNI during which
CIT has developed, 2) period of CNI sparing strategy and 3) period of MMF
monotherapy. The following variables were collected: parameters of liver graft
function (prothrombin time, albumin, bilirubin, γGT, ALT, AST) and renal
function (calculated creatinine clearance: CrCl). Liver graft and renal
functions were the two end-points. Statistical analysis used paired-T tests
(Wilcoxon and T tests).
Results:
52 pts (9F, 43M, mean age: 57 yrs) were treated with MMF
monotherapy. MMF was introduced at a mean of 67 months after liver
transplantation (LT) and the mean time of follow-up during MMF monotherapy
period was 42 months. The reasons for being treated with monotherapy were CRF
in 88% and metabolic disorders in 12% of cases. Indications for LT were 31%
alcoholic cirrhosis, 31% HCV cirrhosis, 21% HCC, and 13.5% for other reasons.
In term of liver graft function, mean bilirubin, albumin, prothrombin time and
γGT did not change significantly between the three periods. Mean AST and
ALT decreased from 72 and 73 IU/L to 49 and 40 IU/L (p=0.01 and 0.006
respectively) during the sparing period and to 37 IU/L and 34 IU/L (ns) during
the monotherapy period. Only 2 pts experienced acute rejection during MMF
monotherapy (incidence of 4%) leading to CNI introduction. Seven deaths were
recorded (myocardial infarction, sepsis shock, recurrent alcoholic cirrhosis
and cholangiocarcinoma). In term of renal function in pts who developed CRF
(n=46), CrCl decreased significantly from 90.1 to 50.4 mL/min during the first
period (p<0.000001), remained unchanged during the sparing period (50.4 to
43.7 mL/min, p=0.8) and increased significantly from 43.7 to 50.2 mL/min
(p=0.02) during the MMF monotherapy period. Mean variation of CrCl during
monotherapy period was +6,6 ml/min (mean gain of 15,4%). Five pts (11%)
required dialysis despite CNI withdrawal.
Conclusions:
This study showed that MMF monotherapy prevents subsequent
CRF without any sign of major graft dysfunction. Further studies are warranted
to confirm that MMF monotherapy is an attractive strategy in liver recipient
pts with CIT.
587. Liver Transplantation for Hepatocellular Carcinoma: Validation of the Milan Criteria using the UNOS database.
M.
Jatoi; S. Puhl; V. Thyagarajan; S. Pelletier; J. Magee; P. Jeffery; F. J.
Robert; L. S. Anna; J. Marrero.
Introduction:
Liver transplantation (OLT) for hepatocellular carcinoma
(HCC) has been shown to be effective if the Milan criteria are applied. Our aim
was to evaluate the effectiveness of OLT for HCC in the United States.
Methods:
We analyzed the UNOS database since 1998 for all patients
listed for HCC. Demographic, laboratory, clinical, and tumor characteristics
were obtained at the time of listing. Kaplan-Meier analysis was performed from
the time of listing in an intent-to-treat analysis, up to a post-OLT follow up
in December 2005.
Results:
Since 1998, 7365 patients with HCC were listed for OLT, of
these 5106 (69%) were transplanted, 1435 (20%) were removed due to death or
tumor progression, and 824 (11%) removed due change in center or lost to follow
up. The median waiting time for transplant was 90 days and median time before
dropping out was 187 days. 66.3% of patients were listed after the MELD
exception was implemented, leading to a lower dropout rate than in the pre-MELD
era (9% vs. 19%, p<0.0001). The 1- and 5-year survival for all patients
listed for HCC was 81% and 48%, respectively. For patients meeting Milan
criteria the 1- and 5- year survival from listing was 86% and 51%,
respectively, and for those exceeding the Milan criteria but meeting the
expanded UCSF criteria the 1- and 5-year survival was 74% and 16% respectively
(p<0.0001 Milan vs. UCSF, Figure). Patients meeting Milan at listing still
had a better survival when only evaluating patients that underwent transplant.
The dropout rate for those meeting Milan at listing was lower than those
exceeding Milan (9% vs. 17%, p<0.0001).
Conclusion:
About 20% of patients will dropout from the waiting list due
to death or tumor progression. OLT for HCC is effective but the greatest
benefit belongs to those that meet Milan criteria. The UNOS data do not support
expanding the criteria for transplanting HCC.
589. Non-standard livers to liver transplant candidates: a fatal combination in liver transplantation.
A.
W. Avolio; S. Agnes; A. Gasbarrini; E. Nure; M. Siciliano; L. Zileri dal Verme;
R. Gaspari; M. Castagneto.
Background:
The Model for End-stage Liver Disease (MELD) has been adopted
by OPTN (Organ Procurement and Transplantation Network) in the 2002 as the
standard priority rule for the liver transplantation (LTx) waiting list.
Aim:
Aim of the present study is the evaluation using Kaplan-Meier
life tables and Cox regressions analysis of graft survivals after liver
transplantation in relation to MELD score and to donor characteristics
(standard donor vs non-standard donor).
Materials and Methods:
MELD and PELD scores of 244 consecutive grafts were
retrospectively calculated. The MELD score was calculated for 230 adult cases
(age 12-65). The PELD score was calculated for 14 pediatric cases (age 1-11).
All stage II HCC cases where classified as MELD 24. No other correction for the
etiology of liver disease was performed. Grafts used for re-LTx were not
included. Cases were categorized according to the MELD score levels. We
retrospectively identified 3 categories: Low MELD (scores <12, N=60);
Intermediate MELD (scores between 12 and 24, N=155); High MELD (scores ≥25,
N=29). All pts were transplanted using deceased donors (DD). Grafts were
categorized also according to donor quality: standard livers (N=188), vs non-standard
livers (N=53). Non-standard livers were identified by age >=60, or at least
by 2 of the following conditions: a) severe hemo-dynamic instability, b)
ultrasound evidence of steatosis, c) levels of Na >=150 mEq/L, d) period of
ventilatory support >7 days.
Results:
MELD scores of candidates transplanted using standard livers
(18.4±6.9) were similar to MELD scores of candidates transplanted using
non-standard livers (18.2±7.1). In standard livers, the 6-month graft survival
(GS) for the low, intermediate and high MELD classes were 82%, 79% and 78%
respectively; differences did not reach a statistical significance. In
non-standard livers, the 6-month GS for the low, intermediate and high MELD
classes were 90%, 61% and 43%, respectively; differences between low MELD class
and both intermediate and high MELD classes were significant (p<0.05).
Beside donor quality (χ2=6.424 p=0.011), Cox regression analysis
identified 2 independent predictors of graft survival: 1. donor age
(χ2=6.005, p=0.014); 2. recipient creatinine (χ2=6.005, p=0.003).
Conclusions:
Following the different survival figures obtained for each
MELD class at different levels of donor quality, we strongly suggest to avoid
the use of non-standard livers for patients with high MELD scores (≥24).
Nevertheless, we are indeed in favour of continuing the use of non-standard
livers for patients with MELD score <25.
590. Post-Transplant Ascites Typically Occurs in the Absence of Significant Fibrosis.
B.
Y. Lan; G. M. Landry; V. O. Tan; A. Bostrom; S. Feng.
Introduction:
Ascites (ASC) after liver transplantation (tx) is uncommon
but causes substantial morbidity and mortality. Unlike pre-tx ASC which occurs
in the setting of cirrhosis, post-tx ASC can occur in the absence of
significant fibrosis. We identified risk factors for post-tx ASC and reviewed
liver biopsies (bxs) to determine fibrosis stage (st) and characterize
histopathology.
Methods:
Records of 372 adult liver txs performed from 1/98 to 12/02
at a single large center were reviewed to find recipients with clinically
significant post-tx ASC. Logistic regression identified donor, recipient (R),
and tx risk factors for ASC. A pathologist scored all allograft bxs during ASC
episodes.
Results:
Of 372 adult liver txs, 23(6.2%) developed post-tx ASC:
18/173(10.4%) of HCV txs and 5/199(2.5%) of non-HCV txs. Logistic regression
models identified 4 independent risk factors for ASC (Table 1): R female
gender, HCV disease, grade 3 pre-tx ASC, and cold ischemia time ≥ 8
hours. The 23 txs had 25 ASC episodes; 24/25 had allograft bxs. The majority,
17/24 (71%) had fibrosis st ≤2(15=st 0/1; 2=st 2); 7/24 (29%) had
fibrosis st ≥3. Bxes without significant fibrosis did not exhibit
distinctive parenchymal or vascular histopathology (Table 2). ASC in the
absence of significant fibrosis occurred earlier after tx, at a median of 196.5
days (range 13-1174 days) versus 932 days (range 574-1477 days); p=.002. At the
time of ASC diagnosis, renal function for those with and without significant
fibrosis were comparable (Cr 1.7 ± 1.3 vs 1.6 ± 0.52; MDRD GFR 40.1 ± 18.4 vs
36.6 ± 10.6).
Summary:
Female gender, HCV disease, grade 3 disease pre-tx ASC, and
CIT ≥ 8 were strong and independent predictors of ASC which occurred in
6.2% of all liver tx recipients. Intriguingly, the majority (71%) of post-tx
ASC episodes occurred without significant fibrosis and distinctive parenchymal
or vascular histopathology.
592. Outcome of liver transplantation in patients with glutathione S-transferase T1 donor/recipient mismatch and de novo immune hepatitis.
J.
Sousa; I. Aguilera; I. Wichmann; F. Gavilan; J. Pascasio; T. Ferrer; M. Sayago;
A. Nuńez-Roldan; J. Marquez; A. Bernardos.
Aim:
To evaluate the clinical course of liver transplant patients
with glutathione S-transferase T1 (GSTT1) genetic mismatch (positive donor/null
recipient) that our group has recently described as a risk factor for the
pathogenesis of de novo immune hepatitis (IH).
Patients and methods:
280 patients that underwent liver transplantation were
followed for a period >6 months. The GSTT1 genotype was determined in
recipients and donors. Detection of anti-GSTT1 ab was confirmed in WB with the
human recombinant protein. We searched for any association between the four
possible combinations of GSTT1 genotypes, production of anti-GSTT1 ab, de novo
IH and IgG kappa monoclonal gammopathy (Fisher test). We also analyzed survival
of the patients comprising the GSTT1 mismatch that developed de novo IH versus
those that did not (Kaplan-Meier curve).
Results:
44 of 280 patients (17.5%) belonged into the null
recipient/positive donor category. 18 of the 44 (40.9%) produced anti-GSTT1 ab
mean 14 (3-82) months after the transplant and 26 did not; 10 of the 18 were
diagnosed of de novo IH with a mean of 20 (6-60) months. None of the 239
patients included in the other three categories (+ rec/+ donor, + rec/null
donor and null rec/null donor) did ever produce anti-GSTT1 ab or suffered de
novo IH (p<0.0001).
13 of the 18 (72.2%) with anti-GSTT1 ab revealed monoclonal
gammopathy IgG kappa while the 26 without ab did not (p<0.0001). At the time
of diagnosis 6/10 (60%) had cirrhosis attributable to de novo IH. They had a good
response to steroid treatment with a survival rate of 90% after a median
follow-up of 48 months (14-89) from diagnosis. No significant differences were
observed in the survival rate of patients with IH compared to those without the
disease.
Conclusions:
1. The GSTT1 mismatch + donor/null
recipient is a necessary condition but is not sufficient to trigger antibody
production and de novo IH after liver transplant.
2. The IgG kappa monoclonal gammopathy
could be used as a marker of anti-GSTT1 ab and de novo IH.
3. During the follow-up of liver
transplant patients with this mismatch, routine exam of antibodies should be
performed.
4. Despite the cirrhosis stage, medium
and long-term prognosis of de novo IH is good in patients under steroid
treatment.
GSTT1 donor /recipient
genotype
|
|
-/+ |
+/+ |
-/- |
+/- |
|
No response |
45 |
178 |
13 |
20 |
|
de novo IH |
0 |
0 |
0 |
10 |
|
anti-GSTT1 ab |
0 |
0 |
0 |
18 |
Distribution of the four
possible donor/recipient GSTT1 combinations and specific immune response.
593. Post Liver Transplant Quality of Life as a function of pre-transplant MELD score and other variables.
V.
Misra; L. Munsch; R. Mangus; J. Tector; J. Fridell; R. Vianna; S.
Liangpunsakul; M. Alsatie; S. Bhardwaj; B. Musick; B. Juliar; P. Kwo.
Introduction:
The MELD score was adopted to rank liver transplant
recipients based on pretransplant mortality for liver patients using 3
objective variables to improve organ allocation. The optimal MELD score for OLT
is unknown but patients(pts) are typically offered transplant with MELD scores
>15. One limitation of MELD is the exclusion of variables that may affect
QOL (quality of life) including hepatic encephalopathy (HE). Our AIM was to
correlate pre-transplant MELD score and other pre-transplant variables with
post-transplant QOL score.
Methods:
In this single-center, prospective cohort study, pts who
underwent OLT after MELD implementation and were at least one year post-OLT
were consented and administered the SF-36 QOL form to assess measure of disease
(MOD), psychological distress/well being(PDW), personal function(PF),
social/role function(SRF) and general health perception(GHP). MELD score on day
of OLT, grade of hepatic encephalopathy(HE), Child Pugh’s Score(CPT),
hepatoma(HCC) and etiology of liver disease data were obtained from medical
records. Data were analyzed using SAS software. QOL scores were compared
between pre-transplant MELD groups(<16 and >16) using t-test. Linear
regression was used to test the association between QOL outcomes and other
variables adjusted for MELD scores including CPT scores, HE(0-4 based on
grade), HCC and different etiologies. In those with HCC, MELD score was
calculated rather than using score exceptions.
Results:
We present data from the first 100 pts who completed the QOL
questionnaire with mean age 54.3 years (range 19.5-74.3), 66% male. 34% had
returned to work either part time or full time. QOL scores by level of MELD
score are presented in Table 1 with no differences seen in QOL scores between
pre-transplant MELD scores < 16 and > 16. MOD (β=6.86, p=0.007)
&SRF (β=1.47, p=0.035)& scores were higher and PF (β=-0.70,
p=0.026) scores were lower in pts with HCV related liver disease compared to
pts without HCV. GHP scores were lower in pts with higher CTP (β=-0.28,
p=0.016) and in marginally associated in pts with higher HE scores
(β=-0.44, p=0.069).
Conclusion:
Post transplant QOL scores in various domains were not
different in those with pre-transplant MELD scores <16 and > 16. Those
who received OLT for HCV related disease had worse QOL. Higher pretransplant
CTP scores were also associated with worse QOL post OLT.
|
QOL |
Mean Score (Range) for MELD<16 |
Mean Score (Range) for MELD 16+ |
P value |
|
MOD |
22(1-55) |
17(3-41) |
0.076 |
|
SRF |
4.6(0-15) |
4(0-13) |
0.864 |
|
PF |
1.48(0-4) |
1(0-4) |
0.622 |
|
PDW |
7(0-17) |
5.6(0-18) |
0.178 |
|
GHP |
7(0-10) |
7(2-10) |
0.466 |
594. Experience with Pre-Recovery Liver Biopsies in Potential Deceased Liver Donors.
M.
Shaughnessy; P. Weber; R. Menza; K. Bradley; D. Kinder; C. E. Freise.
Purpose:
As the demand for liver transplantation increases, more
marginal donors are being evaluated and their livers recovered for transplant.
Unfortunately, the chance of finding a liver at the time of organ recovery that
may not be transplantable is greater with marginal donors. We hypothesized that
the use of pre-recovery liver biopsies (PBX) in donors thought to be marginal
may help decrease aborted recoveries (donor recovery initiated but liver not
removed), and may facilitate the placement of livers to the most appropriate
patients. We examined the results of our practice over the last 15 months, and
compared liver utilization in this era to the previous three years.
Methods:
The use of pre-recovery liver biopsies began 1/2005, and the
time period of study extends to 4/2006. Indications for biopsy included BMI
>/= 32, ultrasound or CT scan suggestive of fatty infiltration of liver,
significant ETOH history, positive HCV serology, or clinical indications
suggestive of liver disease. Biopsies were performed at the donor hospital, and
read by the local pathologist if available, and in many cases re-read at one of
the transplant centers. An initial report was available as the liver was being
allocated.
Results:
In the 15 months since the biopsy protocol was initiated,
there were 338 potential liver donors, 80 underwent PBX. The mean age (49.9 vs.
36.2 yrs) and BMI (30.0 vs. 25.5) of donors undergoing PBX was significantly
greater than non biopsy donors (p<0.0001). In the group of donors undergoing
PBX, there were only 2 aborted donors, 14 livers were not placed, 4 were
recovered but not transplanted, 1 was ruled out for other medical reasons, and
the remaining 59 livers were transplanted. Macro vesicular fat >30% was the
most common finding on livers that could not be placed. With PBX, there was a
significant drop in the rate of aborted donors compared to the 3 years prior to
initiating the protocol (p<0.0296). There was an increase of 38 livers
transplanted in the first year of the PBX protocol, compared with the previous
year. The biopsy procedure was also safe, with no serious bleeding complications
in this cohort of 80 donors.
Conclusion:
A pre-recovery liver biopsy protocol was successfully used in
our large donor service area, with a significant decrease in aborted donors. The
information available from the biopsies may facilitate placement of livers, and
increase livers transplanted.
597. Sexual dysfunction in female patients before and after liver transplantation (LT).
P.
Burra; A. Masier; D. Canova; G. Germani; M. D'Aloiso; G. Sturniolo; U. Cillo;
F. Montorsi; A. Salonia.
Introduction:
Sexual dysfunction has been scarcely investigated in female
patients with liver cirrhosis. The aim of this study was to investigate the
sexual function in female patients with liver cirrhosis before and after LT.
Methods:
27 female patients with liver cirrhosis evaluated for LT and
20 female patients after LT consecutively followed-up in our outclinic were
enrolled in this cross-sectional study. The control group comprises 13 age-comparable
healthy controls. A medical history and liver disease scores
(Child-Pugh-Turcotte-CPT, MELD) were obtained and all patients filled in a set
of questionnaires on sexual function: Female Sexual Function Index (FSFI); Beck
Depression Inventory (BDI); American Urological Association Symptom Index
(AUASI). Statistical analysis was performed by student’s t test and chi square
test.
Results:
The two groups of patients and the group of controls were age-comparable
(mean±se: before LT 54.54±3.08 vs after LT 50.6±5.2 vs controls 54.1±3.6
p=0.48). 24/27 (88.8%) cirrhotic patients and 19/20 (95%) transplanted patients
filled in the FSFI. Cirrhotic patients and transplanted patients showed a lower
score for sexual desire compared to healthy controls (before LT 2.6±1.2 vs
after LT 2.6±1.2 vs healthy controls 4.0±1.2; p=0.01). No urological
dysfunction was reported in cirrhotic and transplanted patients. Among
cirrhotic patients a significant correlation (p=0.010) between sexual
dysfunction and depression but not between sexual dysfunction and urological
symptoms was observed. In transplanted patients a significant correlation
(p=0.02) between depression, sexual desire and lubrication was observed. BDI,
FSFI and AUASI score do not correlate with aetiology or severity (CPT and MELD
score) of liver disease.
Conclusions:
Female patients with liver cirrhosis, waiting for LT but also
following LT, report a lower sexual desire as compared to healthy controls.
Different domains of sexual dysfunction correlates with depression in both,
cirrhotic and transplanted female patients. No correlations were found between
sexual dysfunction and aetiology or severity of liver disease before liver
transplantation. Studies to investigate the role of hormones in causing the
sexual dysfunction are ongoing.
602. Tacrolimus versus Cyclosporine Based Immunosuppression in Hepatitis C Patients after Liver Transplantation: Long-Term Follow-up of a Randomized Controlled Trial.
P.
G. Northup; T. W. Chong; J. C. Iezzoni; S. E. Kerr; A. S. Burns; T. L. Pruett.
Introduction:
Cyclosporine has been recently shown to have significant in
vitro effects on the hepatitis C virus and these effects are not seen with
tacrolimus. We present long-term follow-up on HCV positive liver transplant
recipients randomized to either cyclosporine or tacrolimus based
immunosuppression with respect to HCV disease activity and progression.
Methods:
57 patients with active hepatitis C infection undergoing
liver transplantation participated in a randomized controlled trial comparing
immunosuppression with cyclosporine (n=28) or tacrolimus (n=29) in addition to
corticosteroids. Recipients who survived more than one year and had at least
one biopsy after transplantation were included in the final analysis (n=45).
Standardized immunosuppression protocols were followed and corticosteroids were
routinely discontinued within six months of transplantation. Protocol liver
biopsies and HCV RNA levels were performed on all patients and were analyzed at
yearly intervals after transplantation. Blinded pathology review of liver
biopsy specimens was performed and HCV grade (0-18) and stage (0-6) were
quantified using the modified Ishak scoring system. Clinical outcome variables were
also compared between groups.
Results:
The mean age was 48y (± 8), 34 (76%) patients were male, and
mean follow-up was 48.5 mos (± 28.3). There was no difference in the proportion
of patients in each group treated with HCV specific therapy after transplant
(p>0.5). There were no statistically significant differences between groups
in HCV RNA levels at years 1 through 5 post-transplant. The mean total
necroinflammatory grade at the end of follow-up in the cyclosporine group was
4.1 versus 4.5 in the tacrolimus group (p=0.45). The mean fibrosis stage was
2.4 versus 2.2 (p>0.5) in the cyclosporine and tacrolimus groups,
respectively. Three patients in the cyclosporine group and 5 patients in the
tacrolimus group eventually progressed to cirrhosis (p=0.47). In the patients
that had disease progression, the mean days to increase 2 points or more in
necroinflammatory score was not different between groups (1502 vs. 1202,
cyclosporine vs. tacrolimus, p>0.5) nor were the mean days required to reach
at least stage 3 fibrosis (1130 vs. 1861, p=0.22).
Conclusions:
This study found no differences in progression of hepatitis C
in clinical, viral load, or histopathology endpoints between cyclosporine and tacrolimus
treatment groups after liver transplantation. Larger studies are required to
further investigate the effect of specific immunosuppression drugs on hepatitis
C.
603. Growth and final height after pediatric liver transplantation in relation to age and underlying disease.
R.
Scheenstra; R. J. Odink ; W. Gerver ; H. Soest ; P. M. Peeters; P. J. Sauer; H.
Verkade.
Introduction:
It is still unresolved to what extent liver transplantation
(LTx) at pediatric age restores growth velocity and affects final height. In
our national program, we have adhered to annual follow up after LTx, which
allows assessing its effects on growth and final height.
Aim:
To determine the effects of pediatric LTx on growth and final
height, in relation to age at LTx, underlying disease (cholestatic vs.
noncholestatic) and immuno-suppressive scheme (cyclosporine/prednisolon vs.
tacrolimus/prednisolon).
Patients and Methods:
Longitudinal data were available of 101 patients for 2 years
after LTx at child age (mean age 3.7 ± 5.4 yr), and of 63 patients for 5 years.
Data on final height were available for 23 patients. Height was determined just
before LTx, and at 2 and 5 years after LTx. Height was expressed as a standard
deviation score of the target height of each individual patient, i.e. their
genetic potential (SDSth).
Results:
Before LTx, patients were growth retarded (median and range
SDSth: -1.6, -6.3 to 1.7), with 40 patients (39%) having a SDSth below 2.
Growth during 2 or 5 years after LTx, expressed in ΔSDSth, was
significantly, positively correlated with pre-transplant growth retardation
(2yr: p<0.001, r=0.63; 5 yr: p<0.001, r=0.62). Nevertheless, at 2 years
after LTx, 29 patients had still a SDSth below -2 (29 %) and at 5 years after
Ltx, 14 patients had a SDSth below –2 (21%). Twelve of the 23 patients reaching
their final height, had a final height < -1.3 SD of their target height SDS,
of which 3 even below -2.0 SD. Underlying cholestatic disease was associated
with more severe growth retardation before LTx (SDSth -2.0 vs. -1.2, p<
0.05), and with better growth in the first two years after LTx (ΔSDSth
+0.6 vs. -0.1, p<0.05), compared with non-cholestatic patients. There was no
significant effect of either age at LTx or immunosuppression scheme on growth
after LTx.
Conclusions:
Growth retardation is a common finding in children before
LTx, particularly in children afflicted by a cholestatic disease. Catchup
growth after LTx was only prominent in cholestatic children that had been
severely growth retarded before LTx. Our longitudinal data indicate that after
LTx at pediatric age, ~50% of patients reach a final height lower than -1.3 SD
of their genetic potential.
604. MELD-XI: a rational approach to “sickest first” liver transplantation in cirrhotic patients requiring anticoagulant therapy.
D.
M. Heuman; A. A. Mihas; A. Habib; H. S. Gilles; R. Stravitz; A. J. Sanyal; R.
A. Fisher.
Introduction:
Priority for “sickest first” liver transplantation (LT) in
the US is determined by the Model for End stage Liver Disease (MELD). MELD is a
good predictor of short-term mortality in cirrhosis, but can overestimate risk
when INR is artificially elevated by anticoagulation. An alternate prognostic
index omitting INR is needed in this situation.
Methods:
We retrospectively analyzed survival data for 554 cirrhotic
veterans referred for consideration of LT prior to 12/1/03 (training group).
Using logistic regression we derived a predictive formula for 90-day
pretransplant mortality incorporating bilirubin and creatinine but omitting
INR. We normalized this formula to the same scale as MELD using linear
regression. This yielded MELD-XI (for MELD excluding INR) = 5.11 ln(bilirubin)
+ 11.76 ln (creatinine) + 9.44. Accuracy of MELD-XI was validated in a holdout
group of 278 cirrhotic veterans referred after 12/1/03, and in an independent
validation dataset of 7,203 cirrhotic adults listed for LT in the U.S. between
5/1/01 and 10/31/01.
Results:
MELD-XI and MELD correlated well in training, holdout and
independent validation cohorts (r=0.930, 0.954, and 0.902, respectively). In
the holdout cohort, c-statistics of MELD vs. MELD-XI for mortality at various
time points were, respectively, 30-day: .939 vs .906; 60-day: .860 vs. .841;
90-day: .842 vs .829; 180-day, .795 vs .797. In the independent validation
dataset, c-statistics for MELD vs. MELD-XI as predictors of 90-day survival
were, respectively, .857 vs. .843 in non-cholestatic liver diseases and .905
vs. .894 in cholestatic liver diseases. Comparable MELD and MELD-XI scores were
associated with comparable prognosis.
Conclusion:
MELD-XI, despite omission of INR, is nearly as accurate as
MELD in predicting short-term survival in cirrhosis. In patients treated with
oral anticoagulants, substitution of MELD-XI for MELD may permit more accurate
assessment of risk and more rational assignment of “sickest first” priority for
LT.
605. Racial Differences in Liver Transplantation and Mortality in Hospitalized Cirrhotic Patients with Portal Hypertension.
G.
Nguyen; D. Segev; P. J. Thuluvath.
Introduction:
It has been suggested that there may be racial disparities in
the use of liver transplantation (LT) in the United States. In this study, we
characterized racial disparities in LT among hospitalized cirrhotic patients
with portal hypertension using a large national dataset.
Methods:
We queried the Nationwide Inpatient Sample, the largest
all-payer dataset of hospital discharges in the U.S., from 1998 to 2003, to
identify hospitalized patients with cirrhosis complicated by portal
hypertension. International Classification of Diseases, 9th Revision, Clinical
Modification (ICD-9-CM) diagnosis codes were used to identify individuals with
a primary diagnosis of portal hypertension or one of its manifestations: hepatic
encephalopathy, ascites, or variceal bleed. ICD-9-CM procedural codes were used
to identify LT and portosystemic shunt procedures. Logistic regression was used
to determine the influence of race on LT, portosystemic shunt procedure, and
in-hospital death while controlling for confounders.
Results:
Baseline characteristics of hospitalized patients with
cirrhosis complicated by portal hypertension are shown in the table below.
Compared to whites, the odds ratios of undergoing LT were 0.30 (95% CI: 0.18 –
0.52) and 0.48 (95%CI: 0.26 – 0.89) for African Americans (AAs) and Hispanics,
respectively, after adjustment for age, gender, calendar year, insurance,
comorbidity, disease manifestation, and geographic region. Similarly, the
adjusted odds ratio for receiving a portosystemic shunt was 0.36 (95%CI: 0.27 –
0.49) and 0.70 (95% CI: 0.54 – 0.88) for AAs and Hispanics, respectively.
Compared to whites, AAs experienced higher in-hospital mortality (OR=1.13:
95%CI: 1.02 –1.3) while Hispanics had a lower risk of death (OR=0.80; 95%CI:
0.72 – 0.88). Among variceal bleeders, the odds ratio for death was 1.8 (95%CI:
1.2 – 2.4) for AAs compared to whites.
Conclusions:
African Americans and Hispanic patients were less likely to
receive LT or a portosystemic shunt than whites. Further studies are warranted
to elucidate the underlying reasons for these disparities to ensure equitable
access to LT for all races.
Baseline
Characteristics by Race
|
|
White |
AA |
Hispanic
|
|
Mean Age ±SE |
59.2 ± 0.2 |
54.8 ± 0.2* |
57.2 ± 0.4* |
|
Charlson Index ±SE |
4.2 ± 0.02 |
4.3 ± 0.04* |
4.3 ± 0.04* |
|
|
N (%) |
N (%) |
N (%) |
|
Female |
16282 (39) |
2941 (42)* |
4201 (35)* |
|
Medicaid |
7038 (17) |
2280 (33)* |
3660 (31)* |
|
Variceal Bleeding |
3911 (9.3) |
585 (8.4)* |
1090 (9.2) |
|
Encephalopathy |
23701 (57) |
4429 (64)* |
7593 (64)* |
|
Ascites |
21166 (51) |
3106 (45)* |
5283 (45)* |
|
Hepatorenal Syndrome |
1145 (2.8) |
197 (2.9) |
305 (2.6) |
* p<0.01
606. The Development of De Novo Autoimmune Hepatitis (Immune-Mediated Hepatitis) and its Effect on Outcome in Patients With HCV Post-Liver Transplantation .
M.
Fiel; K. Agarwal; N. Elhajj; N. Kontorinis; C. Stanca; S. Thung; T. D. Schiano.
Introduction:
De novo autoimmune hepatitis is increasingly recognized as a
complication after liver transplantation (LT) and at times may have an
aggressive course. We have observed an increasing frequency of this in LT
recipients over the past few years, an entity which we term immune-mediated
hepatitis (IMH). We sought to ascertain the natural history and outcome of IMH
in HCV patients and its response to treatment.
Methods:
The Mount Sinai pathology database covering a 12-year period
(1994-2006) was searched for the diagnoses of IMH and/or the terms “liver
allograft” and “plasma cells”. After excluding cases with acute or chronic
rejection, steatohepatitis and bile duct problem, the remaining biopsies were
blindly reviewed by 2 experienced hepatopathologists (MIF & ST). A
diagnosis of IMH was made in biopsies demonstrating sheets of plasma cells (3+)
or 20-30% plasma cell infiltrate (2+) with associated centrilobular necrosis.
Subsequent biopsies were assessed for fibrosis progression and histologic
resolution. Clinical data was gathered from chart review. Exact test was used
for statistical analysis.
Results:
404 biopsies that contained the specified search terms were found.
Non-HCV LT patients (n=336) and HCV LT patients that had concurrent problems
like cellular rejection, steatohepatitis, or vascular/biliary complications
(n=38)were excluded. 30 patients (20 male, mean age at diagnosis = 54 years)
fulfilling IMH criteria were identified. No cases were found prior to 1999.
Upon clinical presentation of IMH, median AST was 140 IU/L, ALT 116 IU/L and
bilirubin 1.1g/dL. Overall, 16/30 (53%) pts died, developed cirrhosis or
required re-LT (negative outcome). IMH occurred 2-141 months post-LT (median
27). 23 pts had follow-up biopsy; 13/23 had fibrosis progression with 8/13
having negative outcome; 6/10 without fibrosis progression had negative outcome
(p=NS). Ten pts resolved IMH (3 with negative outcome), while 11/13 pts not
resolving IMH did poorly (p=0.01); 9 of these 11 pts were treated with IFN
(p=0.02). 6/10 pts not resolving IMH were treated, with 5/6 doing well; 4 of
these pts were treated with azathioprine. 23/30 pts (77%) were receiving
interferon (IFN) for recurrent HCV or had their immunosuppression lowered
during the preceding 3 months. 80% of the remaining pts had autoantibodies
suggesting a predisposition to autoimmunity.
Conclusions:
The development of IMH in pts with recurrent HCV is
associated with an unfavorable prognosis and may accelerate fibrosis
progression. IMH may be associated with IFN use or tapering of
immunosuppression. Treatment with azathioprine should be considered.
608. MELD SCORE AND SERUM SODIUM IN THE PREDICTION OF SURVIVAL OF PATIENTS WITH CIRRHOSIS AWAITING LIVER TRANSPLANTATION.
M.
Londono; A. Cardenas; M. Guevara; D. De las Heras; M. Navasa; A. Rimola; J.
García-Valdecasa; V. Arroyo; P. Gines.
Background/Aims:
Serum sodium predicts prognosis in cirrhosis and may improve the
prognostic accuracy of MELD score, but the available information is limited. We
aimed to assess the prognostic value of serum sodium in the prediction of
survival at 3 and 12 months after listing in patients with cirrhosis awaiting
liver transplantation and compare its predictive value with that of MELD score.
Patients and Methods:
Three-hundred and eight consecutive patients with cirrhosis
listed for transplantation during a 5-year period were included in the study.
252 were excluded because HCC (15 pts), re-transplantation (48 pts), and
diseases other than cirrhosis (52 pts) End-point was survival at 3 and 12
months before transplantation. Variables obtained at the time of listing were
analyzed for prognostic value using multivariate analysis. Accuracy of
prognostic variables was analyzed by ROC curves.
Results:
MELD score and serum sodium concentration were the only
independent predictors of survival at 3 and 12 months after listing. Low serum
sodium was associated with an increased risk of death in all subpopulations of
patients with cirrhosis categorized according to the major complication
developed before listing. The area under the ROC curves for serum sodium and
MELD score were similar both at 3 months (0.83 vs. 0.79, respectively) and at
12 months (0.70 vs. 0.77, respectively). The addition of serum sodium did not
improve significantly the accuracy of MELD score in the prediction of survival
at 3 and 12 months.
Conclusion:
In patients with cirrhosis awaiting liver transplantation
serum sodium concentration shows a good correlation with survival. The addition
of serum sodium does not appear to improve the accuracy of MELD score in
predicting 3 and 12 month survival in these patients.
609. Predictors of Employment in Liver Transplant Recipients.
S.
Saab; C. Wiese; A. B. Ibrahim; F. Durazo; S. Han; H. Yersiz; D. G. Farmer; R.
Ghobrial; L. I. Goldstein; M. J. Tong; R. W. Busuttil.
Background/Aim:
In the United States six thousand liver transplants are
performed yearly, leading many to focus on the enormous cost of
transplantation. Particular attention has been made to the employment status of
liver transplant recipients as an indirect measure of society’s ability to
regain lost expense, and as a marker of a patient’s mental and physical health.
The aim of this study is to determine the factors affecting
employment/subemployment after liver transplantation.
Methods:
Adult liver transplant recipients who were seen at UCLA’s
Pfleger Liver Institute during a nine month period between August 2005 and
April 2006 were administered two questionnaires: one regarding work history and
insurance coverage, and the second a SF-36 (Short Form 36). Through
multivariate analysis, factors significantly associated with employment were
identified.
Results:
The mean age of participants was 51 (standard deviation [SD]
= ± 13.9). The majority (98/204) were transplanted for viral hepatitis. 98.5%
reported having health insurance. 34% had disability coverage. Of 204 subjects,
163 (80%) worked prior to transplantation, and 64 (31%) worked post-transplant.
Of those employed post-transplant, most (29%) returned to work greater than 24
months after transplantation. Eight recipients changed jobs after
transplantation (12.5% of those employed) and 22% had a salary decrease. Only
4% had an increase in salary post-transplant. Thirteen participants reported
having been denied employment secondary to their transplant. In multivariate
analysis, higher post-transplant salary (OR=0.55, 95% confidence interval [CI]
0.45, 0.60, p<0.001), lack of disability prior to transplant (OR=0.49, 95%
CI 0.30, 0.81, p<0.005), and ability to pay for transplant without insurance
(OR=0.53, 95% CI 0.31, 0.89, p=0.017), and matriculation in school (OR=0.25,
95% CI 0.07, 0.89, p=0.032) were independently significantly associated with
post-transplant employment. Employment prior to transplantation, age, type of
insurance, etiology of the liver disease, and MELD scores were not
significantly related to post-transplant employment. In addition, components of
SF-36 survey were not associated with employment.
Conclusion:
Liver transplant recipients are more likely to work after
transplantation if they are students, have a higher post-transplant salary, did
not require disability prior to transplantation, and were able to pay for
transplantation without insurance. Mental and physical health status, and type
of pre-transplant insurance did not affect employment after transplantation.
610. CCR2 V64I Polymorphism: A risk factor for patients suffering HCV after orthotopic liver transplantation?
J.
. Knaak; A. Lautem; C. Moench; G. Otto.
Introduction:
CC-Chemokines may play a key role in the recruitment of
leukocytes during ischemia-reperfusion damage and acute rejection following orthotopic
liver transplantation (OLT). Therefore the CC-chemokine-receptor 2 (CCR2), its
functionless CCR2-V64I-polymorphism (amino acid chance at codon 64. valine
-> isoleucine) and the ligand CCL2 (MCP-1) might have an influence on the
grafts pathology after OLT.
Material and Methods:
In 267 patients after OLT between 09/97 and 08/05 the CCR2
was analyzed with regard to the CCR2-V64I by realtime-PCR (Fluorescence
resonance energy transfer DNA hybridization – light cycler instrument Roche).
CCL2 was measured in patients serum with ELISA .
Results:
219 patients (Alter: 50,6 ± 11,6; 16-69) showed a normal
receptor whereas 47 patients (Alter: 51,6 ± 10,4; 22-69) suffered from the
CCR2-V64I polymorphism (44 heterozygote, 3 homozygote). 5 year graft survival
was 80% in CCR2-V64I patients and 60% in CCR2 patients (p = 0,08 log rank).
5-year-patient survival was 88% and 75% in CCR2-V64I and CCR2, respectively (p
= 0,11 log rank). Almost all dying patients with the I-Allel died because of
HVC recurrence und HCV related liver failure. HCV positive Patients combined
with I-Allel had a poor Patient and Organ survival (60 and 50%) versus the HCV
positive Patient combined with the V-Allel with an outcome of 75 and 64% (p=
0,11 log rank) . HCV neg Patients had a better outcome. The HCV neg Patient
combined with the I-Allel showed great Patient and Organ survival (97 and 95%)
versus the V-Allel Patients with 76 and 64% (p=0,02, log rank). MCP-1 levels
were significant lower (p<0,01, Wilcoxon/Mann-Whitney-U-test) in patients
with CCR2-V64I (Median: 123 pg/ml) compared to CCR2 patients (Median 148,9
pg/ml).
Conclusion:
CCR2-V64I leads to excellent 5 year graft survival of 92%
following OLT. A significant reduction of MCP-1 levels may lead to a reduced
immunoactivation following transplantation and could be reasonable for these
results. Futhermore, recently published data from Nakayama et al (Nakayama et
al., 2004) propose CCR2 polymorphism to interfere with surface expression of
CCR5. On the other hand there might be an induction of tolerance through the
I-Allel not only towards the graft. We thought of tolerance towards the HCV
virus and more cytotoxic influence from T-Cells to hepatocytes.
611. Steroid-free Immunosuppression in Pediatric Liver Transplantation: A pilot study examining efficacy for prevention of graft rejection.
M.
Al Turaiki; N. M. Kneteman; S. M. Gilmour.
Introduction:
Corticosteroids have been part of almost all
immunosuppression protocols in pediatric liver transplantation. The potential
benefits from steroid free pediatric immunosuppression include improved growth
and bone density but this must be balanced with the potential risk of increased
graft rejection. We report the pilot data on rates of graft rejection in a
cohort of children recently transplanted steroid-free, at the Stollery
Children’s Hospital, University of Alberta.
Patients:
Between July 2004 and February 2006, 21 children were
transplanted on a protocol which included intraoperative dacluzimab 2mg/kg and
1mg/kg day 5 post-transplant; tacrolimus 0.1 mg/kg, aiming for trough levels of
8-10 for the first 4 weeks post-transplant; and mycophenolate mofetil 30
mg/kg/day. These patients were compared to a historical cohort of 27 children
transplanted between January 2001 and June 2004 who received standard
immunosuppression of tacrolimus 0.1 mg/kg and corticosteroids with an
intraoperative pulse, and post-operative 1 mg/kg/day with a wean over 2 week to
0.25 mg/kg/day and .1 mg/kg/day by 3 months post-transplant. Corticosteroids
were routinely discontinued by 6 months post-transplant.
Results:
Both cohorts were comparable in regards to demographic data
such as age, gender, etiology and living related donation. Their rates of
infection, PTLD, graft loss and death were also comparable.
All episodes of rejection in the steroid/tacrolimus cohort
occurred within the first 12 months post-transplant. One patient developed
chronic rejection, within the first 12 months post-transplant and went on to
retransplantation. Biopsy proven acute graft rejection occurred in 11/27 (41%)
in the tacrolimus/steroid cohort and 5/21 (24%) in the steroid-free cohort.
There was no difference between the two groups. In both cohorts, all episodes
of rejection were mild/moderate and graded Banff Criteria 3-5/9.
Conclusion:
Steroid-free immunosuppression is safe and does not increase
the risk of early acute graft rejection. Further follow-up of this steroid-free
cohort will provide data on the potential benefits of improved growth and bone
density.
Demographic and
rejection rates in steroid/tacrolimus cohort (n = 27) versus steroid-free
cohort (n = 21)
|
|
Steroid/tacrolimus |
Steroid-free |
p |
|
Age |
4.6 ± 5.5 |
5.1 ± 5.1 |
.751 |
|
Gender M:F |
15:12 |
9:12 |
.561 |
|
Biliary atresia |
56% |
48% |
.771 |
|
Living donor |
26% |
29% |
.355 |
|
Acute rejection |
41% |
24% |
.355 |
612. Does indication of alcoholic liver disease influence the long-term results of liver transplantation?
H.
Audin; C. Defez; M. Bismuth; F. Chermak; H. Rigole; P. Perney; F. Navarro; D.
Larrey; G. Pageaux.
Introduction:
In the European liver transplant registry, the 5-years
survival rate after liver transplantation (LT) is about 70%. Beyond 5 years,
little is known about long-term results. It has been reported that long-term
results could be worse in patients transplanted for alcoholic liver disease
(ALD).
Aim:
To analyze the complications observed beyond 5 years after LT
and to assess the influence of indication for LT on long-term results.
Methods:
We reviewed records of all patients transplanted between
April 1989 and January 2000, and alive 5 years after LT. The following
parameters were assessed, on one part for the whole population, on another part
comparing patients transplanted for ALD and non ALD: survival, de novo cancer,
renal function, arterial hypertension, cardiovascular complications, alcohol
onsumption.
Results:
175 patients, alive 5 years after LT were analyzed, 122 male,
53 female, mean age 48.3±10.8 yrs. The mean follow-up was 9±4.3 yrs. The main
indications for LT were: alcoholic cirrhosis 56%, post viral cirrhosis B or C
31%, hepatocellular carcinoma 8.8%. For the whole population, the actuarial 10-
and 13-yrs survival rates were 80% and 70%, respectively. Among the 33 deaths
observed after 5 yrs, the main causes were de novo cancer (n=9) and infections
(n=6). The evolution of the prevalence of complications already present at 5
yrs was as follows: hypertension, from 65 to 64%, renal failure, from 40 to
46.8%, severe renal failure, from 4 to 9.1%, de novo cancer, from 9.7 to 20%,
cardiovascular complications, from 12 to 19%. When we compared ALD (n=98) and
non ALD (n=77) patients, there was no difference concerning actuarial 10- and 13-yrs
survival rates: 83 vs. 74%, and 71 vs. 70%, respectively. There was
statistically more cardiovascular complications observed in ALD patients: 22%
vs. 14% (p=0.02), but no differences concerning hypertension, renal failure, de
novo cancer. Beyond 5 yrs, alcohol consumption was described in 34.3% of
patients, always mild in 8 non ALD patients, mild in 28, moderate in 8, and
severe in 15 ALD patients. The type of alcohol consumption, mild, moderate, or
severe, did not influence the occurrence of renal failure, hypertension, de
novo cancers, cardiovascular complications.
Conclusion:
In this study of 175 liver transplant recipients living more
than 5 yrs after LT:
1. the main causes of death beyond 5 yrs
were de novo cancer and infection,
2. patients transplanted for ALD
developed more cardiovascular complications,
3. the intensity of alcohol consumption
was not responsible for poorer outcome.
616. Cost Analysis of Liver Transplantation According to MELD Score.
C. W. Duncan; K. Hess; V.
Zacharias; T. Kaiser; L. Trumbell; G. W. Neff.
Introduction:
The successes recognized in liver transplantation (LTx) over
the last decade have resulted in a marked increase in demand for this
operation. The literature is limited in terms of measuring expenses and
resource allocation. In the following report, we examine this evolving topic by
evaluating costs associated with LTx as they are affected by length of hospital
stay stratified over varying MELD scores at the time of transplantation.
Methods:
A retrospective analysis from January 2004 to May 2006 (28
months) was performed on adult (> 18 years) liver transplant recipients.
Patients were subdivided into four subgroups: MELD < 20, MELD score 20 to
24, MELD score 25 to 29 and MELD scores ≥ 30. Hospital costs were
collected from the transplant facility. MELD score groupings were compared
based on length of hospital stay and costs for both the intensive care unit and
floor ward as well as total hospitalization cost during the inpatient stay for
Ltx.
Results:
Length of stay and associated costs in the intensive care
unit was similar throughout the range of MELD scores. The groups differed when
examining length of stay and costs associated with hospital floor ward
admission as well as total cost of transplant hospitalization. The varying
total costs for the different groups were as follows:
MELD < 20 (n=) = $189,410; MELD 20 to 25 = $182,972; MELD
26 to 29 = $242,609; and MELD ≥ 30 = $253,641. This trend indicates that
as MELD scores escalate, especially greater than 25 points, the cost of liver
transplantation also rises as overall hospital stays lengthen.
Conclusion:
·
When
examining aggregated costs of hospitalization, higher MELD scores are
associated with greater costs as measured by fees during admission for
transplantation.
·
In
a health care environment of increasing cost sensitivity, decisions surrounding
liver transplantation may soon incorporate MELD score as a relevant factor
affecting policy decisions for liver transplantation.
617. Comparative Analysis of Ethnic Disparities in Liver Transplantation for Pediatric and Adult population.
G.
W. Neff; N. Kemmer; V. Zacharias; T. Kaiser; R. Neff; M. Thomas; A. Tevar; N.
Majoras; P. Dryer; J. Buell.
Background:
The reported outcomes between ethnic groups following liver
transplantation (LTx) in adults are speculated to be much worse in the African
American population. Data on ethnic differences in the pediatric population is
lacking. The aim was to evaluate whether there were ethnic disparities in
transplantation rate and post transplant survival in adults and pediatric
groups.
Methods:
A retrospective analysis from the UNOS/OPTN databank between
January 1995 and December 2004 was performed on adult and pediatric liver
transplant recipients. Patients were subdivided into four ethnic groups:
African Americans (AA), Hispanic, Caucasians (Cauc), and other. Patient and
graft survival was calculated using the Kaplan Meier method. Log rank test was
used to compare the survival rates.
Results:
Data from 38,639 Adult and 4,341 Pediatric LTx patients were
reviewed. Demographics and survival information was collected. Of the 38,639
adult recipients, 29,432 (76.1%) were Cauc, 4369 (11.3%) were Hispanic,
2963(7.7%) were AA and the remaining 1875 (4.9%) were of other ethnicities.
Caucasians had a statistically significantly higher transplantation rate than
the other ethnic groups (chi-square test p-value < 0.001). Using the Kaplan
Meier estimates (KM) and Cox regression analysis there was a significant ethnic
difference in both patient and graft survival, for 1-, 3-, 5- and 10 year, with
AA showing a lower rate (p <0.001). Of the 4,341 pediatric recipients, 2461
(56.7%) were Cauc, 797 (18.4%) were Hispanic, 824 (18.9%) were AA and the
remaining 259 (5.9%) were of other ethnicities. Caucasians had a statistically
significantly higher transplantation rate than the other ethnic groups
(chi-square test p-value < 0.001). Unlike the adults, there was no ethnic
difference in patient (p=0.31) and graft (p=0.33) survival, for 1-, 3-, 5- and
10 year.
Conclusion:
These results show that AA LTx recipients have a reduced
transplantation rate and a worse survival when compared to other ethnicities in
the adult population. However, the pediatric populations do not have disparity
differences. This information suggests that further studies are indicated to
identify the causes of racial differences in transplant access and outcomes in
the adult patient populations.
618. Does pre-transplant abstinence duration influence the results of liver transplantation for alcoholic liver disease : an attempt of meta-analysis.
P.
Cerdan; J. Daurčs; P. Perney; H. Rigole; F. Navarro; D. Larrey; G. Pageaux.
Introduction:
After liver transplantation (LT) for alcoholic liver disease (ALD),
the main issue is the likelihood of relapse and its influence on outcome,
because it is the possibility of returning to alcohol use that separates
patients with ALD from those with other forms of chronic liver disease. The
majority of transplant teams require 6 months of abstinence before LT. The role
of the length of pre-transplant abstinence, the so-called 6-month rule, as
predictor of post-transplantation abstinence, is still questionable.
Aim:
To perform a meta-analysis of all published studies about LT
for ALD, which assessed pre-transplant abstinence and post-transplant relapse
in order to objectively evaluate whether they influence patient's outcome.
Methods:
MEDLINE and bibliographic searches identified 140 potentially
relevant articles. Twenty-four studies reporting data on 1712 patients met our
inclusion criteria. A first meta-analysis was performed on 19 studies including
1368 patients to evaluate the risk of post-transplant relapse according to the
pre-transplant abstinence. A second meta-analysis was performed on 5 studies
including 444 patients to evaluate the impact of relapse on patient's survival.
It was impossible to perform a meta-analysis to evaluate the impact of
pre-transplant abstinence on graft' and patient's survival, because there were
only 2 studies. The pooled odds ratio (OR) and 95% confidence intervals (CI)
were calculated from the raw study data using the Yusuf-Peto method. We used a
statistical evaluation of heterogeneity by the chi2-test.
Results:
The first meta-analysis is in favor of a higher risk of
post-transplant relapse when the pretransplant abstinence was < 6 months :
OR 28.23, 95% CI : 20.7-38.4. The second meta-analysis is not in favor of an
influence of post- transplant relapse on patient's survival at 3 and 5 years :
OR 0.62, 95% CI : 0.24-1.56, and OR 1.16, 95% CI : 0.5-2,56, respectively.
However, in the two meta-analysis, there was a significant heterogeneity
(p<0.01), explained by the different definitions of relapse and methods of
detecting relapse.
Conclusion:
Using meta-analysis methods:
a) the potential impact of the duration
of pre-transplant abstinence in LT for ALD remains controversial : probably
predictor of posttransplant behavior, few workable data concerning patient's survival.
b) post-transplant relapse does not
influence middle-term patient's survival. A multidisciplinary approach, beyond
the 6-month rule, is then mandatory to evaluate alcoholic candidates for LT.
622. Predictors of renal failure in patients undergoing
liver transplantation for chronic liver disease.
R.
Malik; K. Cheent; K. Morrison; T. Cross; M. Heneghan; J. O’ Grady; M. Bowles;
P. Muiesan; M. Rela; N. Heaton; E. Sizer; W. Bernal; G. Auzinger; J. Wendon.
Aim:
We report on the incidence and predictors of renal failure in
patients undergoing orthotopic liver transplantation (OLT) for chronic liver
disease over a five year period at a single centre.
Methods:
A retrospective analysis of 422 patients undergoing liver
transplantation for chronic liver disease was undertaken between 2000-2005.
Patients were stratified according to their pre-transplant serum creatinine (Gp
A < 90µmol/L, Gp B 90-120µmol/L and Gp C >120µmol/L). Renal failure was
defined as having a serum creatinine outside the normal range on day 1 and/or
day 7 following surgery (normal reference lab. serum creatinine <120µmol/L).
We further categorised the renal failure into 2 groups depending on the
magnitude of the renal dysfunction following surgery: moderate renal
dysfunction was defined as 120µmol/L< Cr <240µmol/L/renal replacement
therapy (RRT) and severe renal dysfunction defined as Cr >240/RRT.
A variety of pre and post transplant factors were examined
using logistic regression analysis to find factors associated with the development
of renal failure on day 1 and day 7 following OLT.
Results:
There were a total of 202 patients in group A (median Cr -
77µmol/L) in whom 37 developed renal failure (18%). We showed that 26 out of 37
had moderate renal dysfunction, whilst 11 out of 37 had severe renal
dysfunction. In group B (median Cr - 101µmol/L) there were 143 patients of whom
75 developed renal failure (52%){p<0.05}. We calculated that 57 out of 75
had moderate renal dysfunction whilst 18 out of 75 had severe renal dysfunction.
There were a total of 80 patients in group C (median Cr - 141µmol/L) in whom 71
patients developed renal failure (89%){p<0.05}. A total of 40 patients had
moderate renal dysfunction, whilst 31 had severe renal dysfunction.
There was significant correlation for developing renal
failure on Day 1 with pre OLT factors {serum creatinine, CrCl}, and post OLT
factors {APACHE 11 score (on day 1}. A significant correlation for renal
failure on Day 7 was seen with pre OLT factors {serum creatinine, CrCl} and post
OLT factors {APACHE 11 score (on day 1), lactate (on day 1), albumin, INR and
Bili.(all day 7}.
Conclusion:
Serum Creatinine and creatinine clearance both performed
equally well in predicting subsequent renal failure/dysfunction. However, the
normal cut off for serum creatinine in patients with severe chronic liver
disease should be lowered to 90µmol/L. We have also shown a number of post
transplant factors that correlate with the development of renal failure after
OLT.
625. A Randomized Controlled Trial of Cyclosporine Vs Tacrolimus Immunosuppression in Patients Receiving Pegylated Interferon and Ribavirin for Recurrence Hepatitis C Virus Infection after Liver Transplantation: The Preliminary Results..
R.
J. Firpi; C. Soldevila-Pico; G. J. Morelli; V. I. Machicao; C. Levy; R.
Cabrera; S. Fujita; A. W. Hemming; A. I. Reed; N. R. David.
Introduction:
Cyclosporine(CsA) is an immunosuppressive agent used in the
management of liver transplant(LT) recipients. Recent studies have demonstrated
an antiviral effect in vitro in the hepatitis C (HCV) replicon culture system.
Aim:
To determine the effect of CsA vs tacrolimus(TAC) in viral
clearance in LT recipients with recurrence HCV infection during therapy with
combination PEG-interferon and ribavirin.
Methods:
Patients with progressive HCV recurrence (Ishak Stage≥2)
have been enrolled in a single-center study from 2004 to present. Patients are
randomized to stay on TAC or to change to CsA for baseline immunosuppression
with one-month washout period before starting interferon. Both groups received
therapy with PEGα-2a and ribavirin x 48 weeks for genotypes 1, or 24 weeks
for genotypes 2/3. Prior to therapy, immunosuppression is tapered to CsA/TAC
monotherapy. HCV-RNA is assessed at entry, week 12(EVR), 24, 48-weeks(ETR), and
6-months after ETR(SVR). Liver biopsies are performed at inclusion and at the
end of treatment.
Results:
37 patients have been enrolled in the study to date, and 31
patients have reached 24 or 48 weeks of therapy. Of the 31, 24(80%) are men,
24(80%) Caucasian, and 27(90%) genotype 1. The mean age is 53 ± 6 yrs. 27
patients have completed 6-month follow-up after end-of-treatment. EVR was
achieved in 12 patients(8 undetectable, 4 two-log drop) on CsA vs 8 patients(7
undetectable, 1 two-log drop) on TAC(p=0.08). The mean drop in HCV-RNA during
the first month on CsA before initiation of interferon was 2.9 million
IU/ml(p=0.3). The mean drop in HCV-RNA at EVR for CsA and TAC was similar (3.1
vs 3.4 million IU/ml), respectively. ETR was achieved by 8 patients on CsA and
6 on TAC(p=0.23). SVR data was available for 27 patients, 4 patients in each
arm achieved SVR. See table below.
One patient died in the CsA arm due to chronic rejection after initiation of
interferon therapy. Overall adverse events were similar in each group.
Conclusions:
Change from TAC to CsA led to a significant HCV RNA drop and
improvement in EVR; however, no significant changes in SVR at the time of the
analysis. CsA may offer an advantage to TAC in those patients undergoing
PEG-based therapy. Larger randomized-controlled studies are needed to further
investigate these findings.
|
|
TAC |
CSA |
|
Baseline HCV RNA IU/mL (mean) |
3.8 x 106 |
3.2 x 106 |
|
Baseline ALT U/L (mean) |
150 ± 123 |
125 ± 78 |
|
Initial Ishak Fibrosis Score (mean) |
2.1 |
2.9 |
|
Early Virological Response |
8/16 (50%) |
12/15 (80%) |
|
End of Treatment Response |
6/16 (38%) |
8/14 (57%) |
|
Relapse |
0/14 (0%) |
3/14 (21%) |
|
Sustained Virological Response |
4/14 (29%) |
4/14 (29%) |
626. Renal Insufficiency after Liver Transplantation in the MELD Era Compared to the Pre-MELD Era.
Z.
Feng; J. Tang; M. Abouljoud; J. Arenas; K. Brown; S. Gordon; D. Kim; M.
Sherbondy; A. Yoshida; T. Pham; G. Divine; D. Moonka.
Background:
The model for end-stage liver disease (MELD) score for
patients awaiting orthotopic liver transplant (OLT) was implemented in 2002.
Because the MELD system gives priority to patients with a higher creatinine, and
because pre-OLT renal function is an important determinant of post-OLT renal
function, the current study compares the burden of renal insufficiency in the
pre-MELD and MELD eras.
Method:
We identified all OLT patients at our center from 1995 to
March 2005 who underwent an initial liver transplant with graft and patient
survival of at least one year. A total of 354 patients were divided into 211
patients in the pre-MELD cohort and 143 patients in the MELD cohort. We
compared renal function in the two groups using the glomerular filtration rate
(GFR) as calculated by the validated Modification of Diet and Renal Disease
formula. Data on sirolimus conversion, end-stage renal disease (ESRD), and
death were also evaluated. Patients with a combined kidney-liver transplant
were excluded.
Results:
Comparisons between the pre-MELD and the MELD cohorts were
similar in baseline characteristics including age, sex, HCV infection, BMI,
diabetes, and hypertension. Hepatocellular carcinoma was more common in the
MELD cohort than the pre-MELD cohort (21% vs. 6%, P<0.001). The laboratory
MELD score was similar between the two groups. The GFR (ml/min/1.73m2) at the
time of transplant, discharge, and 12 months was significantly higher in the
MELD cohort than the pre-MELD cohort (see table). Actuarial analysis showed no
difference in the two groups in incidence of ESRD. There was improved overall
survival (P=0.045) and a higher rate of sirolimus use (P=0.001) in the MELD
era. While patients who had a combined liver-kidney transplant were excluded
from the analysis, patients were more likely to have a combined transplant in
the MELD era (6.2% vs 2.6%, P=0.071).
Conclusions:
o
The
concern about greater renal insufficiency in the MELD era was not realized at
our institution.
o
Our
comparison of renal insufficiency actually demonstrated an improvement in renal
function in the MELD era at the time of transplant, discharge and month 12.
o
Potential
explanations for this include:
o
A
lack of difference in the calculated MELD scores in the pre-MELD and MELD ears
o
A
higher rate of transplants for hepatic cellular carcinoma in the MELD eara
(21%) compared to the pre-MELD era (6%)
o
An
earlier and greater use of sirolimus in the MELD era
o
A
greater use of kidney-liver transplants in the MELD era (6.2%) compared to the
Pre-MELD eara (2.6%) for patients with advanced renal insufficiency (P=0.071)
o
a higher rate of transplants for HCC, an
earlier and increased use of sirolimus and a greater use of kidney-liver
transplants in the MELD era for patients with advanced renal insufficiency.
|
|
Pre-MELD
|
MELD |
P-valve |
|
GFR at Transplant |
85.3 |
95.5 |
0.041 |
|
GFR at Discharge |
77.4 |
90.4 |
0.002 |
|
GFR at 12 Months |
60.3 |
66.8 |
0.028 |
|
GFR at 18 Months |
58.8 |
63.6 |
NS |
|
GFR at 24 Months |
59.3 |
64.0 |
NS |
627. Evidence that an extension of Milan criteria to 5-5 criteria does not impact survival nor HCC recurrence after liver transplantation for hepatocellular carcinoma.
H.
M. Badran; C. Meyer; R. Adam; A. Plessier; F. Durand; O. Boillot; J. Dumortier;
S. Dharancy; M. Hilleret; T. Decaens; D. Cherqui; C. Duvoux.
Background and Aim:
We recently suggested on a large cohort of pts transplanted
for HCC between 1988 and 1998 that 5-year survival rates were similar (61% vs
55%, p=0.2) between pts within Milan criteria or fulfilling the following
extended criteria : tumors < 5 in number and with max. diameter of the
largest nodule < 5cm*, i.e. the 5-5 criteria.
The aim of this study was to reassess the results of these
extended criteria on a more recent cohort of pts transplanted for HCC in
France.
Patient and methods:
A retrospective analysis of 168 patients transplanted between
1999 and 2001 for HCC without venous obstruction in 7 French centers comprised
133 Milan + pts, and 35 Milan – pts fulfilling the 5-5 criteria. The survival
and recurrence rates, and the tumor features of these 2 groups were compared.
Results:
The 5-year survival rates were similar in the Milan+ pts and
5-5 pts (79.5% vs 80.0% , p=0.46, Log rank test), with a similar rate of
post-operative mortality (6.2% vs 5.7%). HCC recurrence rate did not differ
between the 2 groups (8.9% vs 11.8% p=0.26).
These results were observed despite the following significant
differences between pre-LT tumors characteristics in Milan + and 5-5 pts :
pre-LT AFP : 111.3±439 ng/ml vs 388.2±839.3 p=0.015, pre-LT number of nodules :
1.6±0.8 vs 3.2±1.2, p<0.0001, pre-LT diameter of largest nodule : 2.4±0.9 cm
vs 3.5±1.0 cm, p<0.0001, pre-LT sum of diameters : 3.2±1.3cm vs 6.2±1.4 cm,
p<0.0001. On the explanted liver, all the aforementioned criteria were
comparable between the 2 groups: post-LT number of nodules: 3.1±5.3 vs 4,5±3.6,
p<0.07, post-LT diameter of largest nodule : 3.0 ±2 cm vs 3.5±1.7 cm,
p<0.23, post-LT sum of diameters : 5.5±3.9cm vs 6.8±3.9 cm, p<0.14. The
prevalence of well differentiated tumors were comparable in both groups (64% vs
63%=0.88) and no difference was noted in the rate of micro-vascular invasion
(24.8% vs 32.3%, p=0.54)
Multiple regression analysis revealed that only
micro-vascular invasion (p=0.04, OR 7.8) and degree of differenciation (p=0.03,
OR=12.4) were independently related to recurrence but not the pre or post-LT
size and tumors number, whereas independent factors related to mortality were
age at LT (p=0.028, OR=1.1) and degree of differenciation (p=0.003, OR=7.0).
Conclusion:
This study shows that a moderate extension of transplantation
criteria to HCC < 5 nodules and largest< 5 cm does not impact tumor
recurrence rates and confers an excellent post-transplant survival comparable
to that of Milan positive patients, close to 80%. The 5-5 criteria can therefore
be proposed as extension criteria for LT for HCC.
*
Duvoux et al. AASLD 2005
629. Transjugular Intrahepatic Portosystemic Shunts (TIPS) are Associated with a High 1-year Mortality in Liver Transplant Recipients.
J. J. Kim; R. J. Fontana;
N. L. Dasika.
Background:
Complications of portal hypertension and graft failure are
increasingly being reported amongst liver transplant (LT) recipients with
recurrent liver disease and cirrhosis. The utility of TIPS for post-LT ascites
and variceal bleeding is not well described. The primary aim of our study was
to determine the efficacy and safety of TIPS in LT recipients with advanced
portal hypertension.
Methods:
Between 8/85 and 12/04, 14 of 1266 LT recipients (1.1%) at a single
center underwent TIPS for recurrent variceal bleeding or refractory ascites.
Pre-TIPS laboratory and clinical features as well as post-TIPS outcomes were
retrospectively reviewed.
Results:
14 LT recipients with median age 52 years (r: 13-68 years)
underwent attempted TIPS but 3 were unsuccessful due to technical failure (2 PV
thromboses, 1 IVC stent). 64% were male, 57% had HCV infection, and the median
time from LT was 46 mon (r: 3-183 mon). Amongst the 11 patients undergoing
successful TIPS, the mean lab MELD score was 17.1 ± 5.8 and 6 (55%) had biopsy
proven cirrhosis. Indications for TIPS included refractory ascites in 7 and
bleeding varices in 4. The mean pre-TIPS hepatic portal venous gradient (HVPG)
of 18.3 ± 6.1 mm Hg was significantly reduced to 9.0 ± 3.5 mm Hg post-TIPS (P
<0.01) and 8 (73%) patients achieved an HVPG <12 mm Hg.
However, only 50% of the varices patients had no further
bleeding and 57% of the ref ractory ascites patients required no further
paracenteses. In addition to peri-procedural complications of death in 1
patient and renal failure in 3 others, 4 patients (29%) developed infection.
During follow-up, 9 patients (82%) developed new onset or
worsening encephalopathy at a median of 11 days (r: 2-73 days) post-TIPS. None
of the 14 patients were retransplanted and the actuarial 3-month and 1-year
patient survival was 57% and 14%, respectively. 8 of the 10 deaths (80%) were
liver related while 2 patients died of other causes.
Conclusion:
Liver transplant recipients with refractory ascites and
bleeding can achieve adequate portal decompression post-TIPS but the rate of
peri-procedural complications is higher than that reported in non-LT patients.
Over 50% of patients experienced improved control of ascites or bleeding but 82%
developed new onset encephalopathy. The low 1-year survival following TIPS
placement of 14% indicates that LT recipients with complications of portal
hypertension have a very poor short-term prognosis in the absence of
retransplantation.
631. Prevalence and predominant factor of low bone mineral density among patients awaiting liver transplantation.
T. Liang; X. Bai; L. Wu;
J. Li; S. Zheng.
Introduction:
Hepatic osteodystrophy occurs in the majority of patients
with advanced chronic liver disease and transplant patients experience rapid
loss of bone leading to high fracture rates early after liver transplantation.
BMD is currently recommended method to determine bone mass.
Aim:
The goal of this study was to investigate the frequency and
predictors of low bone mineral density (BMD) among patients awaiting liver
transplantation. BMD of the lumbar vertebrae (L) and femoral neck (F), measured
by dual-energy X ray absorptiometery, were obtained in 64 pre-transplant
patients between September 2005 and March 2006. Markers of bone metabolism
including serum calcium, phosphorus, parathyroid (PTH), bone alkaline
phosphatase, olsteocalcin, and urinary hydroxyproline were assessed as well.
Osteoporosis was defined according to the World Health Organization criteria
for osteoporosis as a T score of less than –2.5 and osteopenia as a T score
between –1 and –2.5.
Patients with osteoporosis and osteopenia were included in
the group of low BMD. Both univariate and multivariate models were utilized for
statistical analysis. P values < 0.05 were considered statistically
significant. No patient had history of fracture in this series. The mean BMD at
L and F were 1.035+0.132 and 0.962+0.150, respectively.
Results:
The mean T score at L and F were -1.2+1.1 and 0.2+1.1,
respectively. Low BMD was found in 36 patients (36/63, 56.2%), including
osteoporosis in 6 (6/64, 9.3%) and osteopenia in 30 (30/64, 46.9%). Of all
variables (gender, age, primary disease-cholestatic versus non-cholestatic,
Child-Tucotte-Pugh classification, model for end liver disease score, serum
calcium, phosphorus, parathyroid (PTH), bone alkaline phosphatase,
olsteocalcin, and urinary hydroxyproline), cholestatic liver disease and high
level of PTH were found to be significantly associated with low BMD by
univariate analysis. Only PTH was identified as an independent risk factor of
low BMD by multivariate analysis. Median PTH was 55.6 pg/ml (range 7.8~337
pg/ml) in the low BMD group compared with 33 pg/ml (range 3~162 pg/ml) in the
non-low BMD group (P< 0.05).
Conclusion:
This study revealed high incidence of low BMD among liver
transplant recipients preoperatively and high PTH was predominant factor
associated with low BMD. Both BMD and PTH should be routinely measured to
identify statues of bone mass and bone metabolism in recipients prior to liver
transplantation, being a guide of prevention and therapy for bone loss
posttransplantation.
633. The Development of Hepatic Granulomas in Patients Receiving Pegylated Interferon Therapy for Recurrent HCV Post Liver Transplantation.
M. Fiel; D. Shukla; N.
Saraf; R. Xu; T. D. Schiano.
Introduction:
Infrequently hepatitis C (HCV) appears to be the cause of
hepatic granulomas. Interferon (Ifn) therapy for HCV has been increasingly
associated with the development of sarcoidosis.
Aims:
We sought to determine the incidence of hepatic granulomas in
patients with recurrent HCV post-LT and to ascertain their potential
significance in response to antiviral treatment.
Methods:
Between 1994-2005, 820 patients were transplanted for HCV at
our institution. The pathology database was searched for patients having
recurrent HCV and granulomas. At Mount Sinai, protocol biopsies have been
performed for the last two years in patients receiving pegylated-Ifn-α-2b
and ribavirin (PEG) for recurrent HCV. Number, location, size of the granulomas
and presence of fibrosis were noted. Review of slides from explanted livers,
pre- and post-perfusion biopsies and all biopsies of the allograft livers were
re-evaluated. Lipogranulomas were excluded because of their frequent
association with steatosis. Patient demographics, and duration of PEG treatment
if any, were recorded.
Results:
10,225 liver biopsies were performed on HCV patients and 25
(0.24%) showed noncaseating epithelioid granulomas. Hepatic granulomas were
detected in 14 post-LT HCV patients; nine patients received PEG. Typically only
one lobular granuloma was found. The granuloma was small, poorly-formed and
often showed entrapment of hepatocytes. None of these patients had granulomas
in the native liver or in any biopsy prior to Ifn therapy; 6/9 patients had
undetectable HCV-RNA levels and 4 had sustained viral response. No other cause
for granuloma formation was identified in the six patients.
Conclusions:
Hepatic granulomas are infrequently found in HCV liver
biopsies and rarely found in post-LT biopsies with recurrent HCV. When present,
they occur more commonly in patients receiving and virologically responding to
PEG therapy. The presence of granulomas in patients with HCV being treated with
PEG does not warrant an extensive etiologic workup for granulomatous hepatitis
unless otherwise clinically indicated.
Patients
with granulomas that had virological response to Ifn
|
Case |
Ifn/Riba
dose |
Duration
of therapy |
Viral
Response |
Time to
treatment response |
Genotype
|
Time to
HG formation (mos) |
Protocol
biopsy? |
|
1 |
180/800 |
12 |
SVR |
8 |
3a |
7 |
yes |
|
2 |
180/1200 |
12 |
SVR |
8 |
1a |
8 |
yes |
|
3 |
135/1200 |
12 |
ETR |
6 |
1a |
12 |
yes |
|
4 |
120/800 |
20 |
SVR |
19 |
1a |
30 |
yes |
|
5 |
135/800 |
42 |
SVR |
39 |
unk |
35 |
yes |
|
6 |
180/400 |
8 |
Currently remains negative |
2 |
1b |
4 |
yes |
ETR = end of treatment
response SVR = sustained viral response
636. Age, creatinine and liver function but not MELD predict 6-month survival after liver transplantation: clinical and economic considerations.
T. Weismueller; H.
Barg-Hock; M. P. Manns; J. Klempnauer; T. Becker; C. P. Strassburg.
Introduction:
Liver transplantation (OLT) is substantially burdened by the
significant shortage of organs. In the Eurotransplant zone (ET) the severity of
liver disease is grouped into medical urgency criteria (MUC) to ensure
necessity-oriented OLT. The group of T2-patients exhibiting 11 Child-Pugh
points or more with a reduced post OLT survival is increasing. Pre-OLT
management therefore requires parameters capable of predicting short term
outcome in an attempt to optimize preoperative management.
Methods:
104 consecutive OLT patients (May 2004 - April 2005) were
analyzed retrospectively and represent a homogeneous cohort without changes in
graft allocation or transplant procedures. Statistical analyses were performed
using Mann-Whitney-test and multiple logistic regression.
Results:
104 patients (61.5% men, mean age 46.3±12.1 years) were transplanted:
25% viral Hepatitis (10.6% Hepatitis B, 14.4% Hepatitis C), 20.2% primary
sclerosing cholangitis, 13.5% alcoholic liver disease, 10.6% metabolic liver
disease (5.8% hemochromatosis), 6.7% primary biliary cirrhosis. 13.5% had
developed hepatocellular carcinoma. 56.7% were ET status T2, 33,7% were T3,
9.6% underwent high urgency OLT. Overall 6-month-survival was 84.6%. The
majority of deaths were because of multi organ failure. T2-patients had a lower
6-month-survival (T2: 81.4%, T3: 91.4%), longer pre-OLT hospitalization
(26.8+-3.7 vs 11.3+-3.1 days, p=0.002) leading to higher costs (€9015.69 vs.
€4276.57, p=0.005). Patients who died within 6 months of OLT were older (52.4 ±
2.5 vs. 45.2 ± 1.3 years, P= 0.041) with lower choline esterase (2.3±0.4 vs.
3.7±0.2 kU/l, P=0.004). Body mass index was not significantly different
(24.8±1.3 vs. 24.5±0.5 kg/m2). Serum-creatinine (P=0.034), sodium (P=0.048) and
choline esterase (P=0.019) but not pre-OLT MELD were independent parameters of
6-month survival. Pre-OLT creatinine >140 mM/L and choline esterase
<2kU/L predicted a 6-month-survival of 70% and 68%, respectively.
Discussion:
The allocation of organs to patients with severe liver
failure has lead to an increase of OLT in patients with a reduced prognosis (ET
T2). Pre-OLT age, creatinine and choline esterase but not MELD are predictors
of short term post-OLT survival. In view of an increased utilization of
resources, higher costs, lower survival rates, and a resulting increase of
waiting time for less critically ill patients (T3) these parameters may be
helpful as a simple bedside score for pre-OLT clinical management, outcome
prediction and decision making.
637. Rate Of Progression Of Portopulmonary Hypertension Over A Short Time Interval In Patients Awaiting Liver Transplant.
S. Khara; A. Samanta; B.
Koneru; D. O'Hare; A. Fisher; A. De la Torre; D. Wilson; M. DebRoy.
Introduction:
Development of pulmonary artery hypertension in patients with
portal hypertension, also called portopulmonary hypertension (PPHTN), carries
significant perioperative mortality with increasing pulmonary artery (PA)
pressure in patients undergoing liver transplant (OLT). New-onset PPHTN in
patients awaiting OLT has recently been reported despite normal PA Pressure at
initial evaluation. This raises important questions about the rate of
progression of PPHTN, which may shed light on its pathophysiology and influence
our assessment of PPHTN. To our knowledge, there are no studies on the rate of
progression of PPHTN using mathematical model of progression of PA
hypertension.
Aim:
Present study is an analysis of patients with PPHTN including
calculation of the rate of progression of PA hypertension.
Material and Methods:
Of 503 patients evaluated by 2D echocardiography from
November 1999 to March 2003, nine had right heart catheterization for PPHTN. Of
these, cardiac catheterization data was available for seven patients, and five
had follow-up 2D echocardiography with sequential PA pressure measurements over
subsequent 3-24 months for calculating the rate of progression of PPHTN. A
linear regression model (y=m x + c, m is the slope and c is the y intercept)
was used to correlate measured PA Pressure against time with slope of the
regression providing the rate of progression of PA hypertension.
Results:
There were 5 females and 2 males. Mean age was 49.3 + 2.8
years (range 42-59). Etiology of liver disease was primary sclerosing
cholangitis, alcoholism and autoimmune hepatitis in one each, chronic hepatitis
C in 2 and cryptogenic in 2. MELD score was 13.2 + 1.3 (range 9-17). Cardiac
output was 7.0 + 1.0 L/min (range 4.6-11.4), base line PA systolic mean
pressure was 56.5 + 6.1 mm Hg (range 30-90), pulmonary vascular resistance was
277 + 52.5 dynes.s.cm-5 (range 178-357) and all had tricuspid regurgitation.
Based on our mathematical model, the rate of progression of PPHTN was 1.06 +
0.3 mm Hg/month and ranged from 0.25 to 2.15 mm Hg/month. There was no
correlation between the rate of progression of PPHTN and either the severity of
liver disease (MELD score) or the hyperdynamic cardiac output.
Conclusion:
The study shows an appreciable rate of progression of PPHTN
in patients awaiting OLT, which is not related either to the severity of liver
disease or to hyperdynamic systemic hemodynamics. Our findings confirm that
PPHTN can be progressive even over a short time interval and support the role
of altered vasomotor tone in the pathophysiology of the disease. The rate of
progression of PPHTN may influence our future practice of assessing PPHTN in
patients awaiting OLT.
640. Liver transplantation for hepatocellular carcinoma over two decades. A single center experience.
R. Goldstein; S.
Chinnakotla; G. Narasimhan; D. Orr; T. Uemura; L. W. Jennings; D. Chase; R.
Ruiz; G. McKenna; H. Randall; E. Sanchez; M. Levy; G. Klintmalm.
Introduction:
This is a report of our 20 years of experience in liver
transplantation (LTx) for hepatocellular carcinoma (HCC) with emphasis on
recent multi-modality approach and results.
Methods:
Between January 1985 and January 2005, 248 primary orthotopic
liver transplants were performed for HCC in patients with coexisting liver
disease who met the UNOS criteria and were not resectable. 163 patients also
received systemic chemotherapy (doxorubicin 10mg/M2) intraoperatively and
postoperatively for 20 weeks. From the year 2000, we added tumor ablative
treatment (chemoembolization; radiofrequency thermoablation, alcohol ablation
or cryoablation) in patients (n=86) awaiting liver transplantation.
Results:
Patients and recurrence-free survival are shown in the Table.
Use of any form of ablative treatment in patients waiting for LTx significantly
improved recurrence-free survival (p=0.0035). Implementation of MELD system for
organ allocation significantly has reduced the waiting times.
Univariate analysis showed that solitary tumors (p=0.0009)
and unilobar tumors (p=0.004) had a significantly higher recurrence-free
survival (Table). Vascular invasion (p=0.0001) had a negative impact on
survival. Tumor size (p=0.0001) correlated with the recurrence-free survival.
Well differentiated tumors (p<0.05) (Grade I & II) had a significantly
better survival than poorly differentiated tumors (Grade III and IV). The
higher the number of nodules (p=0.001) the worse the recurrence-free survival.
Conclusions:
The results of liver transplantation have significantly
improved over the last 2 decades. The shorter waiting period and use of
ablative treatment have significantly contributed to improved results.
|
|
1985-1989
|
1990-1994
(N=49) |
1995-1999
(N=53) |
2000-2004
(N=122) |
P |
|
% Patient Survival 1yr/2yr/5yr |
79/71/37 |
63/53/32 |
73/66/52 |
91/88/77 |
<0.001 |
|
% Recurrence-free survival 1yr/2yr/5yr |
67/50/33 |
57/45/24 |
70/58/47 |
91/89/74 |
<0.001 |
|
Median waiting period in days |
10 ± 8 |
38 ± 78 |
224 ± 160 |
94 ± 333 |
|