Book on hepatitis from page 364 to 375

Book on hepatitis from page 364 to 375

364  Hepatology 2012
clinical and virologic LAM resistance were excluded. Combined nucleos(t)ide
analog treatment started upon wait-listing. The median duration of antiviral therapy
prior to LT was 3.6 months. HBIG (800 IU IM) was administered for only one week
post-transplant. During the study, 19 patients were transplanted, and of those, none
had recurrent HBV during a median follow-up of 11.7 months.
Figure 6. Prophylaxis of HBV recurrence after liver transplantation (LT). Combined use of
nucleos(t)ide analog(s) and hepatitis B immunoglobulin (HBIG) is the current gold standard for
prophylaxis of HBV reinfection after LT. HBIG therapy can be withdrawn in the long term after
LT in selected low-risk (HbsAg-negative) cases. Those who are anti-hepatitis B core (anti-HBc)-positive and without detectable anti-hepatitis B surface (anti-HBs) titers or anti-HBs titers <100
IU/L should be vaccinated according to the German Guidelines (Cornberg 2011). In case of no
or little response (anti-HBs <100 IU/L) to vaccination, lamivudine (LAM) monotherapy can be
initiated. In patients who have protective anti-HBs titers of >100 IU/L, antiviral therapy is not
necessary but long-term monitoring of HBV serology including anti-HBs titers is required. Neg.,
negative; pos., positive.
The same group conducted a study comparing patients who were switched from
HBIG/LAM to LAM/ADV versus those who maintained on HBIG/LAM therapy
(Table 5) (see http://hepatologytextbook.com/link.php?id=9) (Angus 2007). One
patient in the switch group became HBsAg-positive, but remained HBV DNA-negative after 5 months; all others remained HBsAg- and HBV DNA-negative at a
median of 17.2 months from randomization.
In another study, sixteen patients with LAM resistance who had treatment at LT
with LAM plus ADV therapy were investigated (Lo 2005). Half of the patients were
administered HBIG for a median of 24 months. None of them had detectable HBV
DNA, 13 were HBsAg-negative, and 2 without combined HBIG therapy maintained
HBsAg-positive after a follow-up period of 7.7 and 9.5 months, respectively.
A small cohort of non-HBV replicating patients who were switched from
HBIG/LAM (150 mg/d) to ADV (5 mg/d)/LAM (150 mg/d) therapy after a mean
post-LT period of 6.5 months was retrospectively investigated (Neff 2007) (Table 5)
Update in Transplant Hepatology  365
(see http://hepatologytextbook.com/link.php?id=9). The mean length of follow-up
from therapy switch was 21 months. They found that none of the patients showed an
increase in transaminases while on dual nucleos(t)ide analog therapy. Although the
authors mentioned that HBV serologic testing was performed, no results were given
post-therapy switch.
In a recently published study from Hong Kong, HBIG-free monoprophylaxis with
ETV was evaluated. Only 26% of patients had undetectable HBV DNA at the time
of LT. HBsAg loss occurred in 91% within 2 years post-transplant but 13% had
reappearance of HBsAg and 22.5% were HBsAg-positive at the time of their last
follow-up visit (Fung 2011).
The efficacy of a switch after at least 12 months of HBIG/LAM to combination
therapy with an oral nucleoside and nucleotide analog was investigated (Saab 2011).
Estimated HBV reinfection rate was 1.7% at 1 year after HBIG withdrawal.
HBV prophylactic postransplant studies to date are limited, small and with short
follow-up periods (Table 5) (see http://hepatologytextbook.com/link.php?id=9).
Larger prospective studies are needed to show if nucleos(t)ide analogs can be safely
applied in the majority of HBV transplant patients against recurrent hepatitis B
infection. Presently, withdrawal of HBIG prophylaxis and maintenanance with
nuclesos(t)ide analog therapy can be considered in stable HBsAg-negative patients
in the long term post-LT.
There is no rationale for continuing HBIG therapy in case of viral breakthrough
with detectable HBV DNA. The choice of antiviral therapy in patients with HBV
recurrence depends on the current antiviral medication, the viral load, and the
resistance profile. Antiviral drug resistance can easily be established by genotypic
assays that identify specific mutations known to be associated with decreased
susceptibility to particular drugs.
Recurrence of hepatitis C in the allograft
The influence of HCV infection on allograft histology is highly variable. The liver
injury can vary from absent or mild disease despite high viral burden to cirrhosis in
the allograft (approximately 20-30% of recipients within 5-10 years of follow-up)
(Rubin 2011). Patient and graft survival in HCV-infected transplant recipients is
worse compared to those with other indications (Berenguer 2007, Forman 2002,
Testa 2000). After a diagnosis of cirrhosis, the decompensation risk appears to be
accelerated (17% and 42% at 6 and 12 months, respectively) (Berenguer 2000) and
patient survival is significantly decreased (66% and 30% at 1 and 5 years,
respectively) (Saab 2005). Female gender has been reported as a risk factor for
advanced recurrent HCV disease and graft loss after LT (Lai 2011). Several other
factors have been suggested that may accelerate HCV reinfection of the allograft
(Belli 2007, Berenguer 2003, Iacob 2007, Saab 2005) (Table 6).
There are insufficient and somewhat controversial data regarding the relationship
between immunosuppressive agents and clinical expression of HCV  recurrence
(Table 7) (Berenguer 2011). TAC and CSA do not seem to be significantly different
(Berenguer 2006a, Lake 2003, Martin 2004, Berenguer 2011) with respect to their
impact on the course of hepatitis C recurrence. Results from the multicenter ReViS-TC cohort study, conducted in 14 Spanish liver centres, revealed that CSA-based
immunosuppression regimens may be advantageous against viral relapse after
366  Hepatology 2012
antiviral therapy as compared to TAC-based immunosuppression (ReViS-TC Study
Group 2011).
Table 6. Factors that may accelerate histological progression in HCV patients after
liver transplantation.
Donor factors  Recipient factors
Age  Surgical factors (cold/warm ischemia time)
Liver graft steatosis  Age
Gender
Non-caucasian race
High viral load pre-transplant/early post-transplant
Genotype 1b
Muromonab-CD3 (OKT3®)
Bolus corticosteroids
Rapid tapering of corticosteroids
Various studies have demonstrated that slowly tapering corticosteroids over time
may prevent progression to severe forms of recurrent disease (Brillanti 2002,
McCaughan 2003).
Induction with MMF has been associated with more severe recurrence of HCV
(Berenguer 2003). Other investigators have found that MMF has no impact on
patient survival, rejection, or rate of viral recurrence in HCV-infected transplant
recipients based on biochemical changes and histological findings (Jain 2002). In a
recent systematic review, recurrent HCV was less severe in 5/9 studies with AZA
compared with 2/17 with MMF (Germani 2009).  Significantly  better patient
survival and graft survival was shown for HCV-infected patients treated with MMF,
TAC, and steroids than for patients treated only with TAC and steroids, with 4-year
patient survival rates of 79.5% vs. 73.8% and 4-year graft survival rates of 74.9%
vs. 69.5% (Wiesner 2005). MMF in combination with a CNI taper for 24 months
had a positive effect on fibrosis progression, graft inflammation, and alanine
aminotransferase levels (Bahra 2005). This may be due to the antifibrotic effects of
MMF through an antiproliferative effect on myofibroblast-like cells.
Interleukin-2 receptor inhibition can be safely used in HCV transplanted patients
(Togashi 2011, Klintmalm 2007, Calmus 2002) while OKT3 has shown to increase
severity of HCV recurrence resulting in impaired patient and allograft survival
(Rosen 1997).
Sufficient data from randomised controlled studies in HCV patients are lacking
with respect to the role of mTOR inhibitors in patients and graft outcome
(Samonakis 2005, Schacherer 2007, Asthana 2011). Results of one study suggest
that  de novo  SRL-based immunosuppression does not significantly affect the
severity of HCV recurrence (Asthana 2011). A lower fibrosis extent and rate of
progression was found among HCV transplant recipients with SRL as primary
immunosuppression as compared to controls with an SRL-free immunsosuppressive
regimen (McKenna 2011).
Update in Transplant Hepatology  367
Table 7. Factors that may accelerate histological progression in HCV patients after
liver transplantation.
Immunosuppressive agent  Severity of HCV recurrance
Calcineurin inhibitors  No difference between cyclosporin A and tacrolimus
Bolus corticosteroids  Higher risk of fibrosis progression, increase in viral load
Azathioprine    Controversial debate
Mycophenolate mofetil  Controversial debate
Monoclonal CD3-antibodies
(OKT3)
Increased risk of graft failure
Interleukin-2 receptor antibodies  No disadvantage on graft survival
mTOR inhibitors Controversial (reduction of vs. no impact on fibrosis
progression)
Regular histological evaluation of post-transplant chronic hepatitis C in 1-year (or
maximum 2-year) intervals is recommendable to determine the grade of
inflammation and stage of fibrosis. In particular, the biopsy result is important for
therapy decision, to exclude signs of rejection prior to antiviral therapy and to
determine the efficacy of antiviral therapy. In addition, there are some published as
well as ongoing studies evaluating the role of non-invasive measurement of fibrosis
in HCV and non-HCV transplant recipients (Cross 2011, Beckebaum 2010).
IFN α and RBV therapy may prevent the development of HCV graft cirrhosis
(Hashemi 2011, Gordon 2009, Cicinnati 2007b). This treatment is however
associated with more side effects and is far less effective than in the non-transplant
setting. The most applicable treatment strategy is treatment of established HCV
recurrence with PEG-IFN α and ribavirin, which results in an SVR of 20-30%
(Gordon 2009). Preemptive antiviral therapy (Shergill 2005, Sugawara 2004,
Chalasani 2005, Bzowej 2011) has not shown superior effects as compared to
established HCV therapy (Berenguer 2008, Chalasani 2005, Bizollon 2005, Castells
2005, Toniutto 2005) and should only be considered in cases of rapid progression of
HCV infection in the early post-transplant period. Most published studies in the
transplant setting are not controlled, monocentric and/or comprise a small patient
cohort (Shergill 2005, Sugawara 2004, Gane 1998, Kizilisik 1997, Ghalib 2000).
Recently published results indicate that RBV pre-treatment increased the
tolerability of the antiviral treatment, and improved its efficacy in LT patients
(Merli 2011).
The NS3/4 protease inhibitors telaprevir and boceprevir are metabolized primarily
by the cytochrome P450  CYP3A4. Coadministration with CNI metabolised
primarily by CYP3A4 has shown to result in increased dose-normalized CSA and
TAC exposure by ~4.6-fold and ~70-fold (Garg 2011).
Optimal onset, dose and duration of therapy are not known yet. Positive predictive
factors for SVR include use of erythropoietin, patient compliance, treatment with
PEG-IFN (versus standard IFN) and an early histological response (Berenguer
2006b).
The proportion of patients who need a dose reduction of their antiviral therapy
due to anemia or leucopenia may be reduced by the use of erythropoietin or
granulocyte-macrophage colony-stimulating factor (not approved for this
indication). Reported risk of rejection is low if antiviral therapy is closely monitored
368  Hepatology 2012
(Gane 1998, Kizilisik 1997). Therapy needs to be withdrawn in case of significant
histologically-proven rejection.
Recurrence of cholestatic liver diseases and autoimmune
hepatitis
Data about the frequency of recurrent cholestatic and AIH-related liver disease vary
in the literature depending on the follow-up period and criteria chosen for definition
of disease recurrence.
The post-transplant prognosis for PBC patients is excellent, with an
approximately 80% 5-year survival reported by most large centres (Carbone 2011,
Silveira 2010). It has been reported that HLA-A, -B, and -DR mismatches between
the donor and the recipient decrease the risk of disease recurrence in PBC patients
(Morioka 2007a, Hashimoto 2001). A recently published study reported recurrent
PBC in one-third of patients at 11-13 years post-transplant (Charatcharoenwitthaya
2007). Various other studies reporting recurrent PBC are depicted in Table 8 (Jakob
2006, Liermann-Garcia 2001, Montano-Loza 2010, Hytiroglou 2008).
Table 8. Recurrence rates in patients transplanted for autoimmune-related or
cholestatic liver disease.
Reference  Patients, n  Follow-up after liver
transplantation
Recurrence
rate
AIH  Duclos-Vallée 2003   17  >120 months  41%
AIH  Prados 1998   27  mean 44 months  33%
AIH  Molmenti 2002  55  median 29 months  20%
AIH  Campsen 2008  66  median 81 months  36%
AIH  Vogel 2004   28  mean 100 months  32%
PBC  Charatcharoenwitthaya 2007  154  mean 130 months  34%
PBC  Jakob 2006  100  up to 17 years  16%
PBC  Liermann-Garcia 2001   400  mean 56 months  17%
PBC  Montano-Loza 2010  108  mean 88 months  26%
PBC  Hytiroglou 2008   100  mean 44 months  16%
PSC  Cholongitas 2008   69  median 110 months  13%
PSC  Alabraba 2009   230  median 55 months   24%
PSC  Vera 2002   152  median 36 months  37%
PSC  Graziadei 1999   150  mean 54 months  20%
PSC  Goss 1997   127  mean 36 months  9%
Diagnosis of PBC in the transplanted liver is usually more challenging than
diagnosis in the native liver. Immunoglobulin M and anti-mitochondrial antibodies
(AMA) often persist, and elevated cholestatic enzymes may be due to other causes
of bile duct damage such as ischemic cholangiopathy or chronic ductopenic
rejection. Recurrent PBC is a histological diagnosis, typically appearing as
granulomatous cholangitis or duct lesions. The frequency of recurrence will be
considerably underestimated if a liver biopsy is carried out only when clinical
features are apparent.
Some investigators have found that CSA-based immunosuppressive therapy is
associated with lower PBC recurrence rates as compared to TAC-based
Update in Transplant Hepatology  369
immunosuppression (Wong 1993,  Montano-Loza 2010). However, long-term
survival has been shown to be not significantly different between CSA-and TAC-treated patients (Silveira 2010). The impact of UDCA on the natural history of
recurrent disease remains unknown. In the Mayo Clinic transplant cohort, 50% of
recurrent PBC patients receiving UDCA showed normalization of serum alkaline
phosphatase and alanine aminotransferase levels over a 36-month period compared
with 22% of untreated patients (Charatcharoenwitthaya 2007). Although no
significant differences in the rate of histological progression could be detected
between the treated and untreated subgroups, the proportion of individuals with
histological progression was significantly lower in those that showed improvement
of biochemical parameters regardless of treatment.
The reported recurrence rate for PSC after LT ranges between 9% and 37%
(Cholongitas 2008, Alabraba 2009, Vera 2002, Graziadei 1999, Goss 1997). A
British liver transplant group found significantly better recurrence-free survival
rates in patients who underwent colectomy before or during LT and in those with
with non-extended donor criteria allografts (Alabraba 2009).
Recurrent PSC is diagnosed by histology and/or imaging of the biliary tree and
exclusion of other causes of nonanastomotic biliary strictures. Histopathological
findings in PSC include fibrous cholangitis, fibro-obliterative lesions, ductopenia,
and biliary fibrosis. In a study conducted by the Mayo clinic, recurrence of PSC was
defined by strict cholangiographic and histological criteria in patients with PSC, in
whom other causes of bile duct strictures were absent (Graziadei 2002). However,
due to the lack of a histological gold standard, the diagnosis of PSC recurrence is
based primarily on cholangiographic features. Due to its responsiveness to steroid
therapy, IgG4-associated cholangitis instead of suspected or recurrent PSC should
be considered in patients with atypical features including history of pancreatitis.
Interestingly, despite immunosuppression, a significantly higher corticosteroid
requirement was reported in the transplant as compared to the nontransplant setting,
with 20% of PSC patients becoming corticosteroid dependent after LT (Ho 2005). A
recent study reported that maintenance steroids (>3 months) for ulcerative colitis
post-LT were a risk factor for recurrent PSC (Cholongitas 2008).
AIH recurrence has been reported in about one-third of patients within a post-transplant follow-up period of ≥5 years (Mendes 2011, Tripathi 2009, Duclos-Vallee 2003, Campsen 2008, Vogel 2004). Incidence increases over time as
immunosuppression is reduced (Prados 1998). A long-term follow-up study (>10
years) by a French group found AIH recurrence in 41% of the patients. The authors
recommended regular liver biopsies, because histological signs precede abnormal
biochemical liver values in about one-fourth of patients (Duclos-Vallee 2003). The
diagnosis of recurrent AIH may include histological features, the presence of
autoantibodies, and increased gamma globulins. The majority of published studies
did not confirm a post-transplant prognostic role of antibodies in  patients
undergoing LT for AIH. Conflicting data exist regarding the presence of specific
HLA antigens that predispose patients to AIH recurrence after LT (Gonzalez-Koch
2001, Molmenti 2002). Histological signs of recurrence include interface hepatitis,
lymphoplasmacytic infiltration, and/or lobular involvement. In an analysis of data
from 28 patients with AIH, 5-year survival rate was not significantly different from
controls with genetic liver diseases (Vogel 2004). Patients had more episodes of
acute rejection though, in comparison to the control group.
370  Hepatology 2012
Patients with AIH typically receive low-dose steroid therapy after LT. The
transplant centre in Colorado that found that recurrence was not strongly influenced
by steroid withdrawal in their cohort attempts to minimise or stop steroid therapy in
AIH transplant patients (Campsen 2008).
Outcome in patients transplanted for hepatic malignancies
The results of early studies of LT for HCC were disappointing. More than 60% of
patients developed tumor recurrence within the first two transplant years (Ringe
1989). Currently, there are recurrence rates of 10-15% in patients fulfilling the
Milan criteria (Zavaglia 2005). In an analysis of predictors of survival and tumor-free survival in a cohort of 155 HCC LT recipients, histological grade of
differentiation and macroscopic vascular invasion were identified as independent
predictors of survival and tumor recurrence (Zavaglia 2005). Others identified
MELD score >22, AFP >400 ng/mL and age >60 years as negative predictors for
survival in HCC (Sotiropoulos 2008b, Jelic 2010). For patients having an indication
for LT despite exceeding the Milan criteria, the use of marginal grafts or
performance of LDLT has been considered as a reasonable option.
Expansion beyond the Milan criteria to University of California San Francisco
(UCSF) criteria (single tumour <6.5 cm; two to three tumours, none >4.5 cm or total
diameter <8 cm, no vascular invasion) or even more liberal criteria (no portal
invasion, no extrahepatic disease) have been discussed widely (Sotiropoulos 2007,
Silva 2011, Jelic 2010). Centers such as the San Francisco Transplant Group as well
as the UCLA Transplant Group have demonstrated 5-year survival rates of 50-80%
after LT for tumours beyond the Milan criteria but within UCSF criteria (Duffy
2007, Yao 2007).
Recently, the 'up to seven' criteria (with 7 being the sum of the size and number of
tumors for any given HCC) were suggested as an approach to include additional
HCC patients as transplant candidates. However, acceptance of a more liberal organ
allocation policy would result in a further increase of HCC patients on the waiting
list and in denying the use of these organs to other non-HCC patients.
Expansion of criteria in the LDLT setting is even more challenging due to the
donor risk and the risk of selection of tumours with unfavorable biology following
the concept of fast-tracking (Hiatt 2005). Novel molecular biology techniques, such
as genotyping for HCC, may become relevant for determining recurrence-free
survival and improving patient selection but these biomarkers can not yet been used
for clinical decision making.
Recently, a satisfactory outcome and potential survival benefit were reported in
studies and a meta-analysis of controlled clinical trials  with SRL-based
immunosuppression in patients transplanted for HCC (Kneteman 2004, Zimmerman
2008, Toso 2007, Liang 2011). These results are in line with a retrospective analysis
based on the Scientific Registry of US Transplant Recipients, which included 2491
HCC LT recipients and 12,167 recipients with non-HCC diagnoses. Moreover, the
SILVER Study, a large prospective randomized controlled trial, comparing SRL-containing versus SRL-free immunosuppression will provide further results and
details with respect to the impact of SRL on HCC tumour recurrence (Schnitzbauer
2010b).
Neoadjuvant chemoradiation and subsequent LT has shown promising results for
patients with localized, unresectable hilar cholangiocellular carcinoma (CCC) (Rea
Update in Transplant Hepatology  371
2005, Masuoka 2011). In a recently published US study, outcome of 38 patients
who underwent LT was compared to that of 19 patients who underwent combined
radical bile duct resection with partial hepatectomy (Hong 2011). Tumor was
located in intrahepatic bile duct in 37 patients and in hilar bile duct in 20 patients.
Results demonstrated that LT combined with neoadjuvant and adjuvant therapies is
superior to partial hepatectomy with adjuvant therapy. Challenges of LT attributable
to neoadjuvant therapy include tissue injury from radiation therapy and vascular
complications that include hepatic artery thrombosis. Predictors of response to the
neoadjuvant protocol prior to LT need to be determined (Heimbach 2008).
Increasing age, high pretransplant tumor marker, residual tumour size in the explant
>2 cm, tumour grade, previous cholecystectomy and perineural invasion were
identified as predictors of recurrence following LT (Knight 2007).
Metastatic lesions originating from neuroendocrine tumours (NET) may be
hormone-producing (peptide hormones or amines) or may present as nonfunctional
tumours (Frilling 2006, Lehnert 1998). They are characterized by slow growth and
frequent metastasis to the liver, and their spread may be limited to the liver for
protracted periods of time. Most studies in patients transplanted for NET are limited
and usually restricted to small numbers of patients. A recently published analysis
based on the UNOS database including patients transplanted for NET between
October 1988 and January 2008, showed that long-term survival of NET patients
was similar to that of patients with HCC. Excellent results can be obtained in highly
selected patients and a waiting time for LT longer than 2 months (Gedaly 2011).
Long-term results from prospective studies are needed to further define selection
criteria for patients with NET for LT, to identify predictors for disease recurrence,
and to determine the influence of the primary tumour site on patient post-transplant
survival.
Recurrent alcohol abuse after liver transplantation for
alcoholic liver disease
Alcoholic liver disease has become a leading indication of LT in Europe and the
United States. Patient and graft survival is excellent in those maintaining alcohol
abstinence after LT. Severe chronic alcohol consumption after LT significantly
decreases the medium- and long-term survival (Pfitzmann 2007). A recent study has
shown that urine ethyl glucuronide is a reliable marker for detection of alcohol
relapse after LT (Staufer 2011). Studies evaluating recurrent alcohol use have
reported a mean incidence of relapse in one-third of patients ranging from 10% to
50% in up to 5 years of follow-up (Burra 2005).
According to results from the European Liver Transplant Registry (ELTR),
mortality and graft failure were more often related to de  novo  tumors,
cardiovascular and social factors in alcoholic LT patients as compared to patients
transplanted for other etiologies (Burra 2010). The role of the length of pre-transplant abstinence as a predictor of post-transplant abstinence has been widely
discussed. Many studies have assessed possible risk factors for alcoholic relapse
after LT. The following factors have been identified as risks for recurrent alcohol
abuse: a shorter length of abstinence before LT, more than one pretransplant alcohol
withdrawal, alcohol abuse in first relatives, younger age, and alcohol dependence
(Perney 2005). Accordingly, the results from the Pittsburgh Transplant Center
revealed that the prognosis regarding continued abstinence post-transplant is much
372  Hepatology 2012
more favourable for individuals with a diagnosis of overconsumption (abuse) than
for those who meet criteria for alcohol dependence (DiMartini 2008).
A recently published study reported that poorer social support, family alcohol
history, and pretransplant abstinence of ≤6 months showed significant associations
with relapse (Dew 2008). In addition, an Australian study identified the presence of
psychiatric comorbidities, or a score higher than 3 on the High-Risk Alcoholism
Relapse (HRAR) scale as factors predictive of relapse into harmful drinking (Haber
2007).
Experiences with liver transplantation in inherited
metabolic liver diseases in adult patients
LT is regarded as an effective treatment strategy for patients with Wilson’s Disease
which presents as deterioration of cirrhosis not responsive to treatment, as acute on
chronic disease or fulminant hepatic failure (Moini 2010). LT reverses the
abnormalities of copper metabolism by converting the copper kinetics from a
homozygous to a heterozygous phenotype, thus providing an adequate increase of
ceruloplasmin levels and a decrease of urinary copper excretion post-transplant. The
King's College Hospital reported excellent long-term results after LT in patients
who have undergone LT for Wilson’s Disease since 1994 with 5-year patient and
graft survival rates of 87.5% (Sutcliffe 2003). There are several reports in the
literature indicating a reversal of neurological symptoms after LT (Martin 2008).
However, the course of neurological symptoms remains unpredictable and it is still
a matter of debate if LT should be considered in patients with severe neurological
impairment (Pabón 2008).
Αlpha-1-antitrypsin (AAT) deficiency is a common genetic reason for pediatric
LT, but a rare indication in adults. The Z allele is most commonly responsible for
severe deficiency and disease. LT corrects the liver disease and provides complete
replacement of serum AAT activity.  567 AAT recipients who underwent LT
between 1995 and 2004 were retrospectively investigated (Kemmer 2008). Results
based on UNOS data revealed 1-, 3-, and 5-year patient survival rates of 89%, 85%,
and 83%, respectively.
In hemochromatosis, iron depletion therapy prior to LT may be associated with a
better outcome after LT and is therefore strongly recommended (Weiss 2007). It has
been reported that the survival of patients who undergo LT for hereditary
hemochromatosis is markedly lower in comparison to other indications (Dar 2009,
Brandhagen 2001). Reduced post-transplant survival in patients with
hemochromatosis has been attributed to cardiac problems and increased infectious
complications. Findings derived from the UNOS database revealed 1-year and 5-year survival rates of 75% and 64% in patients with iron overload, as compared to
83% and 70% in those without iron overload (Brandhagen 2001). More recent
results from patients with hemochromatosis (n=217) transplanted between 1997-2006 revealed excellent 1-year (86.1%), 3-year (80.8%), and 5-year (77.3%) patient
survival rates, which were not different from those transplanted for other liver
diseases (Yu 2007).
Update in Transplant Hepatology  373
Outcome after liver transplantation for acute
hepatic failure
Acute hepatic failure (AHF) accounts for 5-12% of LT activity worldwide. Drug-induced liver injury due to acetaminophen overdose is the most common cause of
LT for acute liver failure in developed countries (Craig 2010, Au 2011). Other
etiologies comprise idiosyncratic drugs (such as isoniazid/rifampicin, cumarins,
acetaminophen, ectasy, tricyclic antidepressants), Budd-Chiari syndrome, Wilson’s
Disease, hepatitis A, B and E infection or autoimmune disease.
Patients with acute fulminant liver disease should be transferred to an ICU at a
medical centre experienced in managing AHF, with LT capabilities. Bioartificial
hepatic devices may serve as bridging therapy to native liver recovery or to LT.
Early postoperative complications in patients transplanted for AHF include sepsis,
multisystem organ failure, and primary graft failure. Serum creatinine
concentrations above 200 µmol/L pretransplant, non-white race of the recipient,
donor body mass index >35 kg/m
2
and recipient age >50 years have been suggested
as risk factors for post-transplant mortality (Wigg 2005). Others reported that
extended donor criteria rates and severe cerebral edema were associated with worse
outcome (Chan 2009). The Edinburgh LT centre investigated the impact of
perioperative renal dysfunction on post-transplant renal outcomes in AHF patients.
They found that older age, female gender, hypertension, CSA and non-acetaminophen-induced AHF but not the severity of perioperative renal injury were
predictive for the development of chronic kidney injury (Leithead 2011).
The results in patients transplanted for AHF have improved within the last decade
due to the establishment of prognostic models, improved intensive care management
and the option for LDLT which has a limited role in the US and Europe but plays a
major role in Asia (Lo 2008). AHF was the indication for LDLT in more than 10%
of the cohort reported by two Asian groups (Morioka 2007b, Lo 2004).
Available data document that survival in patients with AHF is inferior to that of
recipients with nonacute indications for LT within the first year but comparable in
the long-term (Chan 2009, Wigg 2005).
Conclusion
LT is challenging due to a shortage of organs and a prolonged waiting-list time. The
large disparity between the number of available cadaver donor organs and recipients
awaiting LT has created an ongoing debate regarding the appropriate selection
criteria. The rationale of allocation systems utilizing the MELD score is to prioritize
patients with severe liver dysfunction ("the sickest first"). This results in decreased
waiting list mortality from 20 to 10% in the Eurotransplant region but also in a
reduction of 1-year post-transplant survival by approximately 10%. A potential
modification of the MELD allocation system or rather development of an improved
prognostic scoring system incorporating donor-related factors, pretransplant
mortality and post-transplant outcome is urgently warranted to optimize organ
allocation in the future.
Due to the availability of antiviral drugs, the survival of patients undergoing LT
for HBV infection has dramatically improved and has become comparable to or
even better than the survival of patients with non-virus-related liver diseases. HBIG-
374  Hepatology 2012
free therapeutic regimens with new promising nucleos(t)ide analog combinations
are currently being investigated for their efficacy and safety as first-line therapy in
clinical studies.
HCV has become a leading indication for LT in Europe and the United States.
There is ongoing research aiming to define host or viral factors that predict
recurrence, the impact of immunosuppressive regimens, and the appropriate
timepoint and dosing for combined PEG-IFN and RBV therapy. The overall risk
and benefit of new antiviral treatment strategies including protease inhibitors remain
to be evaluated.
Data about the frequency of disease recurrence in cholestatic and autoimmune
liver diseases vary in the literature. Diagnosis of disease relapse in cholestatic and
autoimmune liver disease is more challenging than in the non-transplant setting.
Most studies report excellent medium-term and long-term results despite limited
therapeutic options for disease recurrence.
LT in HCC patients provides excellent outcomes and low recurrence rates
following the Milan criteria. Expansion of transplantation criteria beyond the Milan
criteria has been discussed at length. The acceptance of a more liberal organ
allocation policy may result in a further increase of the proportion of patients
transplanted for HCC and denying the use of these organs to other patients for
whom better results may be achieved.  Recent developments in genomic and
proteomic approaches may allow the identification of new biomarkers for prediction
of HCC recurrence.
Non-use of alcohol of ≥6 months pretransplant is widely considered the
prerequisite time for listing for LT. There are few reliable predictors of relapse in
alcoholic patients after LT. Survival rates in patients with alcohol-related liver
disease are similar or even better when compared to the outcomes of patients who
undergo transplant for other types of chronic liver disease. In contrast, survival is
worse in patients with heavy alcohol consumption after LT.
The management of cardiovascular, renal, coagulopathic, cerebral and infectious
complications in patients with AHF is clinically challenging. Prognostic models are
helpful but not entirely accurate in predicting those who will require LT. Due to
advances in intensive care medicine and surgical techniques, outcomes for patients
with AHF have progressively improved during the last 2 decades.
Much attention has been directed to reducing CNI-associated long-term
complications. Cardiovascular comorbidities due to metabolic complications such as
diabetes mellitus, dyslipidemia, obesity, and arterial hypertension account for 30-70% of long-term morbidity. Current trends of immunosuppressive strategies
include CNI-sparing/-free protocols including MMF-  and/or mTOR-based
immunosuppressive regimens and corticosteroid-avoidance protocols. CNI delay
with induction therapy for bridging the early postoperative phase should be
considered especially in patients with high MELD scores. Finally, "individually
tailored immunosuppressive" protocols may optimize drug efficacy, minimise drug
toxicity and improve transplant outcome.
Update in Transplant Hepatology  375
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