PART 8: Liver and Pancreas Transplantation
SECTION III
Techniques
CHAPTER 98A
Orthotopic liver transplantation
Kendra D. Conzen, M.B. Majella Doyle, and William C. Chapman
OVERVIEW
Since the initial descriptions of orthotopic liver transplantation
(OLT) in the 1960s, both the number of patients receiving
transplants and the indications for the procedure have increased
significantly. OLT represents the only treatment modality for
many patients with a diverse spectrum of disease, with the pre-
dominant common factor being end-stage liver failure. It also
has become an excellent option as curative therapy for early
stage hepatocellular carcinoma (HCC). Advances in periopera-
tive care of both donor and recipient, organ preservation
methods, and surgical techniques have resulted in a 1-year
overall survival of 88% for all recipients (Wolfe et al, 2010).
Although gains over the last 40 years in the field of hepatic
transplantation are notable, many limitations remain, not the
least of which is the relatively fixed pool of cadaveric organ
donors. Techniques such as living donor liver transplantation
(LDLT), use of non–heart-beating donors, and splitting cadav-
eric grafts may extend the benefit of OLT to more patients
awaiting transplantation.
This chapter presents a broad overview of liver transplan-
tation, including common criteria for recipient and donor
selection (see Chapter 97A), standard operative approaches for
donors and recipients (see Chapter 99), common postsurgical
complications (see Chapter 100), and outcomes related to the
underlying etiology of end-stage liver disease (ESLD). Special-
ized transplant techniques, such as split-liver and living-related
donor liver transplantation, are described in Chapters 98B
and 98C.
PATIENT SELECTION
OLT represents the only curative treatment option for most
patients with irreversible acute and chronic liver disease and
cirrhosis, regardless of cause. Over the past 4 decades, 5-year
patient survival after liver transplantation has increased from
less than 50% to greater than 70% or more (Busuttil et al, 2005;
Jain et al, 2000). The improvement in patient outcome has led
1722
to an expansion in the indications for transplantation and a con-
comitant increase in the number of patients referred to trans-
plant centers (see Chapter 97A). The downside to this success
is the persistent disparity between the number of recipients
vying for a transplant and the number of donor organs available,
a relatively constant supply (Fig. 98A.1).
The number of patients listed for OLT has increased sixfold
since 1993, whereas the number of transplantations performed
increased by only 45% during the same time. In 2008 in the
United States, 15,807 patients were on the waiting list for a liver
transplant, a decline from a peak of nearly 17,000 in 2002
(Wolfe et al, 2010); however, only 5817 of the patients on the
waiting list received a liver allograft, and 90% of these recipients
had a Model for End-Stage Liver Disease (MELD) score above
15 at transplantation (U.S. Scientific Registry of Transplant
Recipients [USRTR], 2008).
Historically, the donor-to-recipient disparity leads to longer
waiting times and worsening medical status with a peak waiting-
list attrition rate of 187 per 1000 patient-years at risk in 1999.
This rate declined by 15% and has remained steady over the
last few years at 160 per 1000 patient-years at risk (Thuluvath
et al, 2010). Because of the limited supply of donor organs,
appropriate recipient and donor selection is paramount to
improve resource use and long-term outcome.
Recipient Selection
Common indications for OLT (see Chapter 97A) include portal
hypertension as manifested by variceal bleeding, ascites,
encephalopathy, hyperbilirubinemia, hepatic synthetic dysfunc-
tion, and lifestyle limitations. More than 70% of liver transplan-
tations are for noncholestatic liver disease, of which the most
common etiologies are viral hepatitis (30%) and alcoholic
cirrhosis (16%) (USRTR, 2008). Biliary atresia is the most
common indication for liver transplantation in patients younger
than 18 years of age (Busuttil et al, 2005; Goss et al, 1998).
Nonalcholic steatohepatitis (NASH) is becoming an increas-
ingly common cause of liver cirrhosis, as the prevalence of
 SECTION III TECHNIQUES Chapter 98A Orthotopic Liver Transplantation
15,000
10,000
5,000
0
1999 2000 2001 2002 2003 2004 2005 2006 2007 2008
Deceased donor Tx
Living donor Tx
Liver waiting list
FIGURE 98A.1. Data from the Scientific Registry of Transplant
Recipients (SRTR), 2009 OPTN/SRTR Annual Report, demonstrates the
persistent disparity between patients on the waiting list and recipients
of deceased-donor and living-donor allografts. The number of patients
awaiting a liver transplant at year’s end decreased after the introduc-
tion of the Model for End-Stage Liver Disease (MELD) and the pediat-
ric MELD allocation system. Tx, treatment.
nonalcoholic fatty liver disease (NAFLD) increases; NAFLD
now affects an estimated 10% of children (Schwimmer
et al, 2006).
Few true, absolute contraindications to OLT exist that uni-
formly portend a poor patient outcome (Box 98A.1). Advanced
cardiopulmonary disease, known extrahepatic malignancy,
uncontrolled systemic sepsis from a source originating outside
the liver, acquired immunodeficiency syndrome (AIDS), and
ongoing or recent substance abuse are absolute contraindica-
tions. Many of the relative contraindications are conditions that
are expected to improve after successful OLT. Examples include
severe hemodynamic instability (e.g., shock) requiring multiple
pharmacologic agents to maintain perfusion and severe hypoxia
uncorrected by conventional intensive care measures in the
context of hepatopulmonary syndrome. Other relative contrain-
dications to OLT are extensive mesenteric venous thrombosis,
morbid obesity, psychiatric disorders uncontrolled by conven-
tional means, absence of a suitable social support network, and
extremes of age (Jain et al, 2000; Loinaz et al, 2002; Rustgi
et al, 2004).
Box 98A.1
Contraindications to Orthotopic Liver Transplantation
Absolute
Advanced cardiopulmonary disease
Extrahepatic malignancy
Uncontrolled sepsis
Active substance abuse
ABO incompatibility
Relative
Hemodynamic instability
Severe hypoxia (except with hepatopulmonary syndrome)
Human immunodeficiency virus infection
Refractory psychiatric disorders
Absence of adequate social support
1723
Increasingly, advances in surgical technique and medical
supportive care are overcoming obstacles and comorbid condi-
tions formerly considered absolute contraindications to trans-
plantation, including portal vein thrombosis (PVT), human
immunodeficiency virus (HIV) infection, and advanced age.
Patients who receive liver transplants now have higher rates of
diabetes mellitus (DM), renal insufficiency, and morbid obesity
(Thuluvath et al, 2010). Although pretransplantation insulin-
dependent DM is not a contraindication to transplantation, evi-
dence suggests that better risk stratification of these patients is
warranted (Thuluvath, 2005). Likewise, patients with extreme
body mass indexes (<18.5 or >40) might be at higher risk for
posttransplantation complications (Dick et al, 2009). Morbid
obesity is also associated with an increased risk of infectious
complications and posttransplantation malignancy.
Although HIV infection has historically been considered a
contraindication to OLT, the advent of highly active antiretrovi-
ral therapy (HAART) has turned HIV into a chronic condition,
and patients are now living long enough to suffer the morbidity
and mortality of other diseases, including ESLD. Therefore
some patients with HIV may be considered for liver transplan-
tation, if their CD4 T-cell count is greater than 200 and their
HIV RNA viral load is less than 50 copies/μL within 12 months
prior to transplantation (Di Benedetto et al, 2008). It should be
noted that hepatitis C virus (HCV) coinfection with HIV pre-
dicts worse outcomes after OLT, with faster and higher rates of
HCV recurrence (Di Benedetto et al, 2008).
The etiology of liver failure may be predictive of outcome
after OLT, although the correlation between preoperative risk
and graft survival sometimes varies. Jain and colleagues (2000)
examined outcomes after OLT in 4000 consecutive patients
treated at the University of Pittsburgh. Patients with metabolic
or autoimmune liver disease experienced 10-year survival rates
greater than 60%, whereas the survival rates for viral hepatitis
or alcohol-induced cirrhosis were 40% to 50%, and patients
transplanted for advanced hepatic malignancy had only a 22%
survival at 10 years. Results for all patients were better in the
most recent era. Earlier contradictory reports notwithstanding,
recipient age probably does not influence transplantation results
significantly (Gayowski et al, 1998; Ploeg et al, 1993; Totsuka
et al, 2004). Thorough screening for medical comorbidities
commonly found in older populations—such as lifestyle-
limiting cardiopulmonary disease, systemic vascular disease,
and chronic renal insufficiency—is crucial to successful OLT in
patients older than 60 years.
The recipient selection process has undergone extensive
revisions to ensure equitable allocation of a scarce resource
(cadaveric donor livers) while attempting to avoid futile trans-
plantation. Before February 2002, recipients awaiting OLT
were prioritized based on the Child-Turcotte-Pugh (CTP)
scoring system (Table 98A.1), time on the waiting list, and
patient location (e.g., intensive care unit). Waiting lists grew
under this system, and it became increasingly clear that these
parameters were not good measures of disease severity.
In 2000, the Department of Health and Human Services
issued a guideline stating that the allocation of livers for trans-
plantation should be based primarily on medical urgency
(Freeman et al, 2002). The United Network of Organ Sharing
(UNOS), which administers the Organ Procurement and
Transplantation Network, commissioned several subcommit-
tees to examine new methods for allocation. The result was the
universal adoption of the MELD criteria (Table 98A.2) as a
1724 PART 8 LIVER AND PANCREAS TRANSPLANTATION Section III Techniques

Table 98A.1 PELD: SPLIT patients

MELD: national waitlist
Child-Turcotte-Pugh Classification
100%
POINTS 90%
1 2 3 80%

Percent survival
70%
Encephalopathy None 1 or 2 3 or 4 60%
Ascites Absent Slight Moderate 50%
Bilirubin (mg/dL) 1 to 2 2 to 3 >3 40%
Albumin >3.5 2.8 to 3.5 <2.8 30%
20%
Prothrombin time 1 to 4 4 to 6 >6 10%
(seconds prolonged)
0%
0 5 10 15 20 25 30 35 40 45 50 55 60 65 70
Severity score
measure of the potential recipient’s necessity for OLT. Concur-
FIGURE 98A.2. Correlation between Model for End-Stage Liver
rent revision of the pediatric liver allocation process produced
Disease (MELD) and the pediatric MELD (PELD) score and patient
the Pediatric End-Stage Liver Disease (PELD) model, which is mortality. SPLIT, Studies of Pediatric Liver Transplantation. (Adapted
discussed further in Chapter 98C. Per a policy change in 2005, from Freeman RB Jr, et al, 2002: The new liver allocation system: moving toward
PELD is applied to potential transplant recipients younger than evidence-based transplantation policy. Liver Transpl 8:851-858.)
12 years. Adolescents aged 12 to 17 years are stratified using the
MELD system.
In contrast to its predecessor, the CTP score, MELD has
been validated extensively as a predictor for 3-month mortality Special considerations for certain subsets of patients with
from chronic liver disease (Malinchoc et al, 2000; Wiesner et al, liver disease are ongoing. Early in the initial evaluation of the
2003a). It incorporates serum creatinine, bilirubin, and interna- MELD criteria, it was recognized that patients with HCC and
tional normalized ratio (INR) as markers for risk of death; early cirrhosis should be prioritized lower on the waiting list,
relies on objective and readily available blood tests; and practi- when they could potentially benefit most from transplantation
cally eliminates time on the waiting list from consideration. (e.g., HCC at an early tumor stage; see Chapter 97D). Conceiv-
Using MELD criteria, rates of death while awaiting OLT and ably, patients with HCC but low MELD scores could develop
removal from the waiting list for being too sick have decreased progressive disease, which would eliminate OLT as a treatment
(Thuluvath et al, 2010). Median time to transplant in 2007 option. Since the most recent revisions to MELD, patients with
was 361 days. stage II HCC currently are allocated 22 MELD priority points.
As shown in Figure 98A.2, the use of MELD criteria for Criteria for selecting HCC patients for transplantation are
predicting mortality from ESLD results in an appropriate discussed further in this chapter, including those with more
correlation between severity score and actuarial survival at 3 advanced stage disease. Guidelines also exist for awarding
months. Survival benefit analysis of liver transplant recipients priority points for other conditions, such as hepatopulmonary
stratified by MELD score demonstrates that the risks involved syndrome, portopulmonary hypertension, hepatic artery throm-
in transplantation are equivalent or less than the risks associated bosis after liver transplant, pediatric hepatoblastoma, inborn
with remaining a transplant candidate on the waiting list with a errors of metabolism, familial amyloidosis, and primary
MELD score over 15 (Merion et al, 2005). The MELD-based oxaluria; however, the process is highly variable by region
allocation process is dynamic and amenable to subtle changes (USRTR, 2008).
to reflect an evolving understanding of the diverse pathology Since 2002, the number of patients on the waiting list with
and physiology seen in patients treated with OLT. exception points for any condition has more than doubled, with
close to 900 on the list in 2008 (Thuluvath et al, 2010). Increas-
ingly, stage I and II hilar cholangiocarcinoma is becoming an
Table 98A.2
acceptable indication for OLT, and uniform criteria for obtain-
Predicted Mortality According to the Model for End-Stage ing MELD exception points have been proposed (Gores et al,
Liver Disease Score* 2006; see Chapter 97E). Eligible patients must be treated
according to a specific protocol that requires neoadjuvant
No. Mortality Death or Removal from
Score Patients Rate (%) List Because of Illness (%) chemoradiation, followed by a staging laparotomy to confirm
absence of N1 disease (Rea et al, 2005).
<9 124 1.9 2.9
10-19 1800 6 7,7
20-29 1098 19.6 23.5 Donor Selection
30-39 295 52.6 60.2 Increased demand for donor organs, as depicted in Figure
≥40 120 71.3 79.3 98A.1, has resulted in the concomitant increase in the use of
*R = (0.957 × Loge [creatinine {mg/dL}] + 0.378 × Loge[total bilirubin mg/dL] + 1.120
less than ideal donors. The theoretic ideal donor is an otherwise
× Loge[INR] + 0.643) × 10 healthy, hemodynamically stable young person who suffers an
D, donor status; R, recipient status; INR, international normalized ratio irreversible cerebral insult that results in brain death; this situa-
Modified from Wiesner R, et al, 2003: Model for End-stage Liver Disease (MELD) tion is rarely realized. Although marginal donors are being used
and allocation of donor livers. Gastroenterology 124:91-96. more frequently, absolute contraindications remain, including
 SECTION III TECHNIQUES Chapter 98A Orthotopic Liver Transplantation
known extracranial malignancy (except for basal or squamous
cell cancer of the skin), overwhelming sepsis, hepatic cirrhosis,
hepatic macrosteatosis greater than 60%, and HIV infection.
Generally, hepatitis B virus (HBV) surface antigen and core
antibody positivity in the donor also constitute absolute contra-
indications (Wachs et al, 1995), although many centers con-
sider transplantation of core antibody-positive livers for
HBV-positive recipients, if the graft seems otherwise suitable,
and even into non-HBV recipients in selected circumstances.
Advanced donor age may adversely affect graft survival, and in
practice, donors older than 80 years usually are excluded from
consideration.
Data that demonstrate differential effects on specific recipi-
ent groups, such as HCV-positive recipients, remain inconclu-
sive (Doyle et al, 2008; Lake et al, 2005; Russo et al, 2004).
Although liver allografts with 30% to 60% steatosis are utilized
in select groups of recipients, it should be recognized that
greater than 60% steatosis significantly increases the risk of
primary nonfunction (Urena et al, 1999). A donor risk index
(DRI) has been developed to help quantify and stratify allografts
by predicted failure risk (Feng et al, 2006).
As a result of the shortage of cadaveric donors, the use of
living donors has increased in the United States, from 1996
with a peak in 2001; it has since declined steadily, and LDLTs
now represent only 4% of liver transplantations performed (see
Chapter 98B). A shift in demographics has also been seen in
recipients of LDLT: patients age 50 to 64 years represent the
largest group (USRTR, 2008). LDLT is appealing, because it
allows elective transplantation after optimizing the health of the
recipient, reduces cold ischemic times, and potentially shortens
waiting times. The disadvantages include morbidity and rare
mortality in the donor population (Brown et al, 2003). The
most common practice in adults is transplantation of the right
hepatic lobe. Despite initial data indicating worse outcomes in
LDLT, a trend has been seen toward improved graft survival
and overall survival in the United States in the last 10 years
(Thuluvath et al, 2010). Although LDLT from an adult to a
child has become well accepted and standardized, adult-adult
LDLT continues to evolve, and the place of this approach as
part of the overall picture of liver transplant options is not fully
defined.
Early reports regarding the successful use of kidneys from
non–heart-beating donors and donation-after-cardiac-death
(DCD) donors encouraged a similar practice in OLT. Most
commonly, DCD donors are patients with severe neurologic
injury, such as anoxia and intracranial hemorrhage, and no
chance for meaningful recovery, yet they do not meet brain-
death criteria; family members and treating physicians must
elect to withdraw support. Donor criteria are similar to cadav-
eric (brain dead) donors.
DCD livers are increasingly being used and now represent
5% of all liver-only transplants (USRTR, 2008). Compared
with historic results with brain-dead donors, outcomes using
DCD allografts are less optimal, with 1- and 3-year graft surviv-
als of 70% and 60%, 10-year graft survival of 44% for all
patients, and a primary nonfunction rate of almost 12% (Abt
et al, 2004; Bernat et al, 2006; D’Alessandro et al, 2000; de
Vera et al, 2009; Mateo et al, 2006; Thuluvath et al, 2010). The
graft survival rate improves when donor warm ischemia time is
less than 30 minutes and cold ischemia time is less than 10
hours (Mateo et al, 2006); however, DCD grafts are associated
with an increased risk of nonanastomotic intrahepatic biliary
1725
strictures (ischemic cholangiopathy) and posttransplantation
hepatic artery stenosis (Chan et al, 2008; Pine et al, 2009).
Given the risks inherent in DCD allografts, they should be used
cautiously in select groups of recipients.
OPERATIVE TECHNIQUES
The first published description of human liver transplantation
was by Starzl and colleagues in 1963 at the University of Colo-
rado. In this seminal paper, the dismal outcomes of three OLT
recipients were described, including one intraoperative death
from uncorrectable coagulopathy and two survivors of 7 and
22 days. In addition to the pioneering conceptual framework
and implementation of liver transplantation, several advanced
techniques are presented in this reference, including the use of
grafts from non–heart-beating donors, venovenous bypass in the
recipients, choledochocholedochostomy, and coagulation moni-
toring using thromboelastography (TEG). Many of these con-
cepts remain or have reentered the realm of liver transplantation
more than 40 years after their initial description. Based largely
on the initial body of work by Starzl and colleagues, this section
describes the surgical procedures commonly used at Washing-
ton University in St. Louis during OLT (see Chapter 99).
Donor Hepatectomy
Management of a cadaveric organ donor begins preoperatively,
immediately after identification of a candidate and after evalua-
tion by trained transplant coordinators. After brain death, severe
physiologic derangements can occur, and physiologic instability
increases in proportion to the length of time between declara-
tion of death and organ procurement (Nygaard et al, 1990).
The progression from brain death to somatic death results in
the loss of 10% to 20% of potential donors (Wood et al, 2004).
Complications that commonly occur in a brain-dead donor
include hypotension, the requirement for multiple transfusions,
disseminated intravascular coagulopathy (DIC), diabetes insipi-
dus (DI), pulmonary edema and hypoxia, acidosis, and arrhyth-
mias and cardiac arrest. Intravascular volume repletion to
normovolemia is the cornerstone of management; however,
vasopressors or inotropic agents often are necessary to achieve
an adequate perfusion pressure. The use of low-dose arginine
vasopressin allows a reduction in the dosing of α-adrenergic
agents, which may impair end-organ perfusion (Pennefather
et al, 1995). Directed therapy using a pulmonary artery cathe-
ter can improve outcome in patients with brain death–induced
or traumatic cardiac dysfunction (Wheeldon et al, 1995). A
thorough review of the medical management of potential organ
donors can be found elsewhere (Wood et al, 2004).
Surgical techniques for procuring abdominal organs from
brain-dead, heart-beating donors have been described previ-
ously (Farmer et al, 2000; Merkel et al, 1972; Starzl et al, 1984,
1987). A midline incision from the suprasternal notch to the
pubis is performed, followed by sternotomy and entry into
the peritoneum. The abdomen is inspected for any evidence of
malignancy or gross gastrointestinal ischemia, which would pre-
clude transplantation. Procurement proceeds in several phases:
warm dissection and cannulation, exsanguination with cold
perfusion and organ removal, and back-table dissection and
organ preparation.
In the warm dissection phase, the liver is mobilized by divid-
ing the umbilical, falciform, and left triangular ligaments.
1726 PART 8 LIVER AND PANCREAS TRANSPLANTATION Section III Techniques
Hepatic arterial anatomy is delineated by inspection of the gas-
trohepatic ligament and porta hepatis to identify aberrant arte-
rial anatomy. A right medial visceral rotation, or Cattel-Brasch
maneuver, is performed, by which the right colon and mesen-
tery of the small intestine are mobilized and reflected toward
the donor left upper quadrant. The infrarenal aorta is exposed
at the bifurcation, and proximal and distal control is obtained.
The inferior mesenteric vein is identified, controlled, and can-
nulated for subsequent portal perfusion.
Next, the intestinal contents are returned to the lower
abdomen with attention turned again to the porta hepatis. The
distal common bile duct is circumferentially dissected, distally
ligated, and transected. The gallbladder is flushed out through a
choledochotomy to clear bile from the gallbladder and biliary
tree to potentially limit injury to the bile duct epithelium. The
common hepatic artery is identified, and the gastroduodenal
artery (GDA) is encircled. After reflection of the left lobe of the
liver medially, control of the supraceliac aorta is obtained, facili-
tated by dividing the diaphragmatic crura.
The entire warm dissection phase usually takes 30 minutes
or less. At this stage, the donor is ready for heparinization
(400 U/kg IV) and for cannulation of the distal aorta, which
occurs in coordination with the other procurement teams.
When the thoracic and abdominal teams are ready, the donor is
exsanguinated via the suprahepatic vena cava. Suction catheters
are placed in the chest to remove warm blood, the aorta is cross-
clamped in the supraceliac location, and the arterial and portal
circulations are flushed—usually with University of Wisconsin
(UW) solution or histidine-tryptophan-ketoglutarate—via the
previously placed cannulae. Infusion continues until the caval
drainage is clear, which typically requires 4 to 5 L via the aorta
and another 1 to 2 L via the portal vein. The donor abdomen is
packed with ice slush for topical cooling during the flushing
phase.
After satisfactory cooling and flushing with preservation
solution, the portal dissection is initiated. The general goals of
this dissection are to delineate the arterial anatomy and dissect
the arterial inflow back to the aorta. This is accomplished by
dividing the GDA, dissecting the common hepatic artery down
to the celiac trunk, dividing the splenic and left gastric arteries,
and dissecting the celiac trunk down to the aorta. This tech-
nique is modified in the presence of a replaced or accessory left
hepatic artery, in which case preservation of the left gastric
artery is mandatory. A search for a replaced or accessory right
hepatic artery also is undertaken through identification of the
superior mesenteric artery and its proximal branches. Preserva-
tion of this artery, if present, is essential.
Next, the portal vein is dissected and divided near the pan-
creas, although a modification is necessary if pancreas procure-
ment is being performed simultaneously. Excision of the celiac
trunk with a Carrel patch of aorta is performed; this common
patch, including the superior mesenteric artery origin, is used if
an accessory or replaced right hepatic artery is present. Atten-
tion is then turned to the infrahepatic inferior vena cava (IVC),
which is divided above the level of the renal veins. As a final
step, the diaphragm is dissected around the suprahepatic IVC.
The diaphragm and all tissues between the right kidney and
liver are divided, and the hepatic graft is removed from the
donor and packed in ice.
The final preparation of the donor graft usually occurs at the
recipient hospital and is a cold, back-table preparation of the
arterial and venous cuffs. This work consists of removal of
the diaphragm and preparation of the suprahepatic IVC. The
adrenal gland is removed, the adrenal vein is ligated, and the
infrarenal IVC is prepared. The portal vein is dissected free
from surrounding tissue up to the bifurcation and is cannulated
for purposes of flushing preservation solution just prior to graft
reperfusion. The celiac trunk is dissected up to the GDA with
all unnecessary branches ligated. During this phase, arterial
reconstruction—that is, donor accessory right hepatic artery to
donor GDA—or conduit creation is performed as indicated. At
this point, the graft is ready for recipient implantation.
Procurement in a DCD donor requires a slight modification
(Bernat et al, 2006; D’Alessandro et al, 2000). In the controlled
setting, the donor is brought to the operating room, and support
is withdrawn. Heparin is administered to reduce risk of throm-
bus formation in the graft (Bernat et al, 2006). Apnea and ces-
sation of circulation ensue after a variable amount of time, at
which point of death is declared. It is important to note that
10% of potential donors do not die within 2 hours of with-
drawal of support; these patients are not candidates for subse-
quent organ donation and are transferred back to the intensive
care unit (ICU) and are allowed to die (Cooper et al, 2004).
Circulation is unlikely to resume after 2 minutes of complete
cessation; a minimum waiting period of 2 minutes is required,
and a 5-minute interval between asystole; pronunciation of
death prior to further intervention is strongly encouraged
(Bernat et al, 2006).
The goal now becomes rapid reperfusion of the organs for
procurement with cold preservation solution; this usually is
accomplished via a quick midline laparotomy and cannulation
of the aorta. Alternatively, some centers use cannulae placed
before death in the femoral artery and vein. Less than 30
minutes of donor warm ischemia time is generally considered
acceptable (Bernat et al, 2006). Hepatectomy is performed as
in a standard brain-dead donor, commonly followed by a
back-table flush. Cadaveric split-liver and living-related liver
transplantation techniques are addressed in Chapters 98B
and 98C.
Recipient Hepatectomy
Removal of the diseased liver from the recipient can be a chal-
lenging technical aspect of liver transplantation. Hepatectomy
often is complicated by marked portal hypertension, coagulopa-
thy, extensive collateralization of venous drainage, a friable liver
that is prone to hemorrhage, portal venous thrombosis, and
possible prior abdominal surgical interventions that may have
included portal venous shunting or biliary tract surgery. Preop-
erative preparation of the recipient includes establishment of
central venous monitoring and intravascular access, ensuring
availability of at least 10 U crossmatched blood, and timely
administration of a second-generation cephalosporin.
Optimal recipient operative exposure is accomplished using
a bilateral subcostal incision with an upper midline extension.
The umbilical, falciform, and left triangular ligaments are
taken down for maximum exposure. The left and right hepatic
arteries are ligated in the hilum as the first step in the portal
dissection. The cystic duct is divided, if needed for exposure,
and circumferential dissection of the common hepatic duct
is performed, which is divided in the mid-extrahepatic
portion. Sufficient distal bile duct length in the recipient is
preserved for the implantation phase, which usually includes
choledochocholedochostomy.
 SECTION III TECHNIQUES Chapter 98A Orthotopic Liver Transplantation
Next, the portal vein is skeletonized proximally to just above
the confluence of the splenic and superior mesenteric vein. At
this point, further dissection is influenced by the use of tempo-
rary portocaval shunting or venovenous bypass; both techniques
allow decompression of the splanchnic circulation, which
reduces bowel edema during the anhepatic phase. When veno-
venous bypass is used, the portal vein is cannulated, and bypass
is instituted as previously described (Shaw et al, 1984). A
potential disadvantage of venovenous bypass is the added com-
plexity and potential complications associated with the bypass
process (e.g., thrombosis of the bypass circuit). We prefer por-
tocaval shunting with an end-to-side anastomosis between the
divided portal vein and infrahepatic IVC. The shunt is kept in
place until the suprahepatic caval anastomosis is completed.
Temporary portocaval shunting in conjunction with the pig-
gyback technique may improve intraoperative hemodynamic
stability and renal function and may reduce the transfusion
requirement (Arzu et al, 2008; Davila et al, 2008; Figueras et al,
2001). If neither venovenous bypass nor temporary portocaval
shunting is used, the portal vein simply can be clamped proxi-
mally, ligated in the hilum, and divided; however, this method
may be associated with a severe reduction in venous return, up
to a 50% decrease in arterial blood pressure, mesenteric venous
hypertension and associated organ failure, and potential
increased hemodynamic instability resulting in intraoperative
mortality (Hoffmann et al, 2009).
With the portal vein bypassed or clamped, exposure for the
infrahepatic dissection and vascular control of the IVC is easily
obtained. The piggyback technique leaves the recipient retro-
hepatic IVC intact and requires ligation and division of all retro-
hepatic caval branches (Tzakis et al, 1989). The advantage of
this approach is that native caval flow is maintained, and veno-
venous bypass is not required; the disadvantage is that division
of retrohepatic caval branches can be tedious and time consum-
ing. The donor suprahepatic IVC is anastomosed to the conflu-
ence of the right, middle, and left hepatic veins, which are joined
in a common cuff. Vascular control is achieved by clamping the
hepatic veins at their point of entry into the vena cava.
Alternatively, if a bicaval technique is used, the recipient’s
native retrohepatic IVC is removed with the native liver. The
retrohepatic IVC is mobilized out of the retroperitoneum from
the left side. The right triangular ligament is taken down, and
the retrohepatic IVC is dissected from the right side. The
adrenal vein is ligated in the traditional bicaval approach;
this dissection frees up the retrohepatic IVC above the hepatic
veins to allow application of infrahepatic and suprahepatic IVC
clamps. The recipient liver is sharply excised with care taken to
leave cuffs of IVC above and below the liver. This technique
allows for true orthotopic placement of the donor graft. Retro-
spective analysis of the bicaval and piggyback techniques
suggest that safety and outcomes are comparable (Nishida
et al, 2006).
Recipient Implantation
OLT requires three or four vascular anastomoses in the follow-
ing order: 1) suprahepatic IVC; 2) infrahepatic IVC, if a bicaval
technique is used; 3) portal vein; and 4) hepatic artery. Alterna-
tively, the use of the piggyback technique allows just a single
caval (end-to-side) anastomosis, with simple ligation of the
donor infrahepatic IVC; this results in a reduction in the
duration of the anhepatic phase (Hosein Shokouh-Amiri et al,
1727
2000). When the liver is fully reperfused, reconstruction of the
biliary tract begins.
Adequate cuffs of suprahepatic and infrahepatic IVC are
essential for reconstruction (Starzl et al, 1979). Anastomoses of
these cuffs require reconstruction of the posterior walls from
within the lumen using a running 3-0 polypropylene suture.
The anterior layer is sutured externally using either an inter-
rupted or a continuous technique. Another advantage of the
piggyback technique is the use of a side-biting vascular clamp
on the IVC at the level of ostia of the hepatic veins. Although
this clamp may impair venous return to the heart to some
degree during a clamp time of 15 to 30 minutes, it generally
produces greater hemodynamic stability during the anhepatic
phase than does complete caval occlusion, which requires a
bicaval procedure (Moreno-Gonzalez et al, 2003). After the
hepatic donor vena cava has been anastomosed to the recipient
IVC, the side-biting clamp can be moved to the graft side of the
anastomosis, restoring complete venous return, while the
remaining vascular connections are performed.
After restoration of caval flow, the portal anastomosis is
undertaken. If venovenous bypass is used, interruption of the
portal circuit is followed by removal of the portal cannula. In
this manner, the donor and recipient main portal veins are
exposed for an end-to-end anastomosis using an everting-cuff
technique. The use of a fine monofilament suture (6-0 or 7-0) is
mandatory. We typically tie this suture with an “air knot” or
“growth factor” of approximately half the diameter of the portal
vein to reduce the likelihood of portal stricture.
The final vascular anastomosis is arterial. The key principle
of hepatic arterialization is to ensure pulsatile inflow through a
large caliber vessel over a short length (Farmer et al, 2000). The
technique involves the use of a fine (7-0) monofilament suture
in a running or interrupted fashion. The vessel ends are fre-
quently spatulated and are sewn from the outside and rotated
to achieve the most precise anastomosis. The presence of aber-
rant hepatic arterial anatomy is encountered in 10% to 30% of
grafts, and preservation of these vessels is essential for suc-
cessful engraftment. Reconstruction of the aberrant vessels to
obtain a single inflow vessel is imperative and takes place during
the back table preparation of the graft as described earlier.
Recipient inflow is obtained from a branch off the celiac
trunk, usually the proper or common hepatic artery. When
adequate arterial inflow cannot be obtained by this artery,
the use of an arterial conduit is recommended. Inflow origi-
nating from the infrarenal and supraceliac aorta has been
described; both methods provide excellent inflow, and the
choice is based on technical considerations and surgeon pref-
erence. The best choice of conduit is usually the donor iliac
vessels. When donor vessels are unavailable or inadequate,
prosthetic conduits can be used, typically polytetrafluoroethy-
lene (PTFE). In the perioperative period, aortic conduits are
associated with increased operating time, greater transfusion
requirements, and respiratory and renal failure (Nikitin et al,
2008). In addition, several cases of internal hernias with small
bowel volvulus around the intraperitoneal conduit have been
reported (Nishida et al, 2002).
Completion of the vascular anastomoses is followed by
establishment of biliary continuity. The most common methods
used are the choledochocholedochostomy or choledochojeju-
nostomy. The technical goals in biliary reconstruction are to
achieve a tension-free anastomosis between viable ducts or
intestine. The method used depends on many factors, including
1728 PART 8 LIVER AND PANCREAS TRANSPLANTATION Section III Techniques
the size match of the donor and recipient common bile duct and
the presence of preexisting biliary pathology. Choledochocho-
ledochostomy is preferable, because after OLT, access to the
biliary tree is easier and safer with ERCP than with percutane-
ous transhepatic cholangiography. Choledochojejunostomy is
used when the above-mentioned technical goals cannot be real-
ized. Most pediatric recipients require choledochojejunostomy
because of small duct size and a history of biliary atresia.
Prior to anastomosis, both the donor and recipient bile ducts
should be trimmed sharply to remove devitalized tissues, and
brisk bleeding should be evident from the cut ends. The recipi-
ent bile duct should be cleared of sludge and stones. Accom-
modation for size mismatch with ductoplasty of the larger duct
or spatulation of both ducts has been described (Buczkowski
et al, 2007; Nissen & Klein, 2009). The choledochocholedo-
chostomy and choledochojejunostomy anastomoses are accom-
plished with the use of fine absorbable monofilament suture in
a single-layer closure.
Whether to stent the biliary anastomosis during OLT is
subject to debate (Barkun et al, 2003; Bawa et al, 1998; Johnson
et al, 2000). Proponents believe that decompression of the
biliary tree reduces the rate of clinically significant leaks,
whereas others point to data that suggest a higher rate of biliary
stricture from internal stents. At our institution, biliary stenting
is performed selectively based on individual case circumstances
and surgeon preferences.
COMPLICATIONS
Complications resulting from OLT can be divided broadly into
technical complications, those arising as a consequence of
immunosuppressive medications, and recurrence or recrudes-
cence of the patient’s original disease. The risk of surgeon-
dependent technical complications increases when more
complex surgical techniques, such as split-liver donation, are
used. Examples of factors generally attributed to technical error
include early thrombosis of the hepatic artery or portal vein,
biliary complications such as leak or stricture, and, to a lesser
extent, primary graft nonfunction. Invasive infection and certain
metabolic complications are side effects of the immunosuppres-
sive regimens currently in use. Finally, subacute and chronic
graft rejection and recurrence of certain causes of initial liver
failure eventually result in graft loss. Each of these complica-
tions is discussed.
Primary Nonfunction
Primary nonfunction is defined as early graft failure after OLT in
the absence of identified technical complications. Clinical pre-
sentation varies, but patients typically are seen with alterations
in mental status, diminished bile production, coagulopathy,
markedly elevated transaminases, and metabolic acidosis. Mul-
tiorgan failure ensues, with oliguria and hypoxia occurring fre-
quently. The reported rate of primary nonfunction varies
between 1% to 7% of all OLTs (Jain et al, 2000; Johnson et al,
2007; Kamath et al, 1991; Kemmer et al, 2007; Taner et al,
2008; Totsuka et al, 2004). Retransplantation is the treatment
of choice and typically is required within 72 hours. Some
authors also report the distinctly separate category of initial
poor function, in which allografts might have a chance for func-
tional recovery; however, no consensus for a clear definition
exists.
The etiology of primary nonfunction is unclear but is likely
multifactorial. Factors commonly reported to be associated
with nonfunction include prolonged cold and warm ischemic
times, donation after cardiac death, intraoperative systemic
hypotension (mean arterial pressure <40 mm Hg), severity of
donor steatosis, advanced donor age, and recipient factors such
as portal vein thrombosis (PVT), renal failure, dependence on
life support, and status 1 listing (de Vera et al, 2009; Fernandez-
Merino et al, 2003; Johnson et al, 2007; Marsman et al, 1996;
Nair et al, 2002; Ploeg et al, 1993; Reich et al, 2003; Sharma
et al, 2010; Strasberg et al, 1994). Although it has been proven
that severe macrosteatosis (>60%) increases risk of graft failure,
the influence of moderate steatosis (30% to 60%) remains
unclear (Yoo et al, 2003a), and such allografts can be used with
careful selection (Doyle et al, 2010).
Donor liver biopsy to quantify graft steatosis should be per-
formed before implantation of any graft that appears marginal
(D’Alessandro et al, 1991). As would be expected, the likeli-
hood of primary nonfunction is increased in the presence of
multiple risk factors (e.g., steatotic graft with extended total
ischemic time) and in allografts with several marginal donor
criteria (Pokorny et al, 2005; Salizzoni et al, 2003).
Hepatic Artery Thrombosis
Hepatic artery thrombosis (HAT) can be broadly divided into
early (acute) and late (delayed) clinical presentation, with differ-
ent etiologies, patient manifestations, and treatments. Although
there is no formal consensus, early HAT is typically defined as
occurring within the first 1 to 2 months after OLT and has a
mean incidence of 2.9% in adult OLT patients, with a signifi-
cantly higher incidence of 8% to 10% in the pediatric popula-
tion (Bekker et al, 2009; Farmer et al, 2007). Early HAT carries
a high risk of graft loss and death—53% and 33%, respectively
(Bekker et al, 2009).
Technical, donor, and recipient factors contribute to an
increased risk of HAT (Bekker et al, 2009; Del Gaudio et al,
2005; Duffy et al, 2009; Jurim et al, 1995; Soin et al, 1996;
Vivarelli et al, 2004). Donor factors may include small-caliber
vessels, aberrant anatomy that requires complex arterial recon-
struction, use of aortic conduits, or cytomegalovirus (CMV)
seropositivity donor-recipient mismatch. Variable recipient
anatomy (e.g., replaced hepatic artery from superior mesenteric
artery [SMA]) also influences risk of HAT.
Although early HAT may be asymptomatic, it frequently
results in massive hepatocellular injury evidenced by increased
transaminase levels and impaired hepatic synthetic function.
The hepatic artery is the sole blood supply to the donor bile
duct; therefore early HAT often presents with bile leak, cholan-
gitis, or sepsis. Duplex ultrasound (US) is diagnostic in virtually
all cases of HAT in adults, although visceral angiography
remains the gold standard. If diagnosis is prompt, emergency
exploration with attempted thrombectomy and revasculariza-
tion may salvage the graft, although this is usually not possible.
Some reports suggest that endovascular procedures—
intraarterial thrombolysis, percutaneous transluminal angio-
plasty, and endoluminal stenting—can be successful in hepatic
arterial revascularization (Singhal et al, 2010); however, a
majority of patients eventually require retransplantation (Bekker
et al, 2009; Duffy et al, 2009). Because of the severity of this
complication, some authors advocate the routine use of post-
operative duplex US.
 SECTION III TECHNIQUES Chapter 98A Orthotopic Liver Transplantation
Late HAT is typically more indolent, frequently because a
previously undiagnosed stricture allows collateral circulation to
develop. Clinical presentation may include fever secondary to
perihepatic abscess or biliary leak, biliary strictures, or cholan-
gitis, although in some cases patients may be asymptomatic
with no clinical consequences (Gunsar et al, 2003). Contribut-
ing factors are active tobacco abuse; coagulation abnormalities,
such as factor V Leiden; cerebrovascular accident as donor
cause of death; donor death at an age greater than 50 years;
recipient CMV positivity; and use of donor iliac interposition
graft (Del Gaudio et al, 2005; Gunsar et al, 2003; Pascual et al,
1997; Pungpapong et al, 2002; Stewart et al, 2009; Vivarelli
et al, 2004).
Treatment may be attempted with endoscopic or percutane-
ous biliary decompression, stenting, or even systemic anticoag-
ulation. Retransplantation is required less for late HAT than for
early HAT. Because postoperative antiplatelet therapy may
reduce the rate of late HAT in high-risk patients (Vivarelli et al,
2007), it is our practice to prescribe daily aspirin (81 mg) for all
patients.
Hepatic Artery Stenosis
Hepatic artery stenosis (HAS) without thrombosis is also a rec-
ognized complication of liver transplantation, with an incidence
of 4% to 11% (da Silva et al, 2008). DCD allografts have been
implicated as a risk factor (Pine et al, 2009). Initial presentation
typically includes a mild increase in aminotransferase levels
with or without associated graft dysfunction or biliary compli-
cations. Doppler US demonstrates increased resistance in
hepatic arterial flow and is often diagnostic, but confirmation
by arteriography is the gold standard. Therapeutic options
include angioplasty with or without stenting. Restenosis can
occur in up to one third of patients within 1 year after stenting
(Ueno et al, 2006).
Portal Vein Thrombosis
PVT occurs less frequently than HAT after OLT, with an inci-
dence less than 2% in adult recipients and 10% in pediatric
recipients (Duffy et al, 2009; Lerut et al, 1987; Millis et al,
1996), although PVT adversely affects overall survival after
OLT (Duffy et al, 2009). Low portal flow, small-diameter veins
(<5 mm), preexisting PVT in the recipient, donor-recipient
vessel size mismatch, and the use of vascular grafts for recon-
struction are known risk factors for developing PVT (Cheng
et al, 2004).
PVT is typically symptomatic, and patients can present with
acute hepatic failure, as with HAT, or with the sequelae of
portal hypertension, such as increasing ascites, splenomegaly,
and variceal hemorrhage (Duffy et al, 2009). Diagnosis is made
using duplex US or contrast-enhanced CT portal venography.
Depending on the timeliness of diagnosis and the acuity of
the patient, several treatment options exist. In patients with ful-
minant hepatic failure from PVT, reexploration and attempted
portal revascularization are performed. These patients some-
times require retransplantation, particularly in the rare setting
of combined PVT and HAT (total absence of hepatic inflow).
The use of a portocaval shunt to augment flow through the
reconstructed portal vein has been described (Bakthavatsalam
et al, 2001), as has the use of transjugular intrahepatic portoca-
val shunt (TIPS) in conjunction with thrombolytics (Ciccarelli
1729
et al, 2001). Systemic anticoagulation may be sufficient in
patients with preserved graft function (Duffy et al, 2009).
Symptoms of portal hypertension but preserved graft function
often can be managed medically with standard therapies for
ascites in combination with variceal banding or sclerotherapy;
however, the graft salvage rate with these alternative strategies is
typically much less than 50% (Duffy et al, 2009).
Portal Vein Stenosis
Portal vein stenosis, in contrast to PVT, is frequently diagnosed
on routine screening US in asymptomatic patients. The most
common area of stenosis is the extrahepatic portal venous anas-
tomotic site. Narrowing of the main portal vein diameter by
more than 50%, presence of a poststenotic jet, or lack of visual-
ized flow on Doppler imaging are diagnostic. Many stenoses
can now be managed with percutaneous transhepatic balloon
angioplasty and stenting (Woo et al, 2007).
Biliary Complications
Biliary complications are the most common type of posttrans-
plantation complication, and they arise in 7% to 29% of liver
recipients. Patients with HAT, living-donor allografts, and DCD
livers are at higher risk for biliary complications (Maluf et al,
2005; Pine et al, 2009; Zajko et al, 1988). Historically, Roux-
en-Y choledochojejunostomy was associated with higher com-
plication rates than choledochocholedochostomy (O’Connor
et al, 1995); however, this remains a controversial topic in trans-
plantation techniques. All patients found to have a biliary com-
plication should undergo US to evaluate HAT as a contributing
factor.
Biliary strictures occur twice as frequently as anastomotic
biliary leaks and can be classified as anastomotic or nonanasto-
motic (ischemic cholangiopathy) (Balsells et al, 1995; Qian et al,
2004). Most anastomotic strictures are managed endoscopi-
cally with balloon dilation and stenting. Ischemic cholangiopa-
thy more commonly results from bile duct ischemia or an
immune response, appears later and affects multiple sites, tends
to be more difficult to manage, and is rarely amenable to endo-
scopic treatment. Nonanastomotic strictures are associated
with a higher rate of graft failure requiring retransplantation
(Chan et al, 2008; de Vera et al, 2009; Pine et al, 2009). A mul-
tidisciplinary approach to diagnosis and management of biliary
complications is necessary and can result in higher patient and
graft survival rates (Verran et al, 1997).
In an asymptomatic patient with stable liver function, biliary
complications can often be managed nonoperatively. Bile col-
lections should be drained percutaneously under US or CT
guidance, and most leaks are controlled with endoscopic stent
placement across the anastomosis (Shah et al, 2004). Major
leaks or total disruption usually requires operative conversion to
a choledochojejunostomy or hepaticojejunostomy, an option
that can result in long-term biliary patency (Langer et al, 2009).
Numerous studies have evaluated the use of T-tubes and
internal stents for prophylactic biliary decompression. Several
have identified T-tube use as an independent risk factor for
increased postoperative biliary complications (e.g., biliary-
cutaneous fistulae and cholangitis), and their use has not been
shown to reduce the need for posttransplantation interventional
procedures (Qian et al, 2004; Scatton et al, 2001; Sotiropoulos
et al, 2009). Consequently, T-tubes are much less commonly
1730 PART 8 LIVER AND PANCREAS TRANSPLANTATION Section III Techniques
used in standard adult OLT in the United States; however, a
recent prospective European trial did not find evidence of
increased biliary complications with T-tubes (Weiss et al, 2009).
The effectiveness of internal stenting in reducing biliary com-
plications also remains inconclusive (Welling et al, 2008).
Infection
Infection is the most common cause of death after OLT at all
time points (Jain et al, 2000), directly causing 28% of all deaths
in liver transplant patients. An autopsy series of OLT patients
showed an even higher infection-related mortality rate of 64%
(Torbenson et al, 1998). Two thirds of OLT recipients experi-
ence at least one serious infectious episode (Winston et al,
1995), despite ever-improving prophylactic regimens. Intraab-
dominal infections occur in 40% of recipients with a higher
incidence in patients with other noninfectious surgical compli-
cations (Reid et al, 2009).
Liver transplant patients are immunocompromised as a
result of antirejection medications, they are also malnourished,
chronically ill, have received multiple blood-product transfu-
sions, and have undergone lengthy and complex surgical
procedures—all of which are risk factors for infectious compli-
cations. Additionally, the risk of posttransplantation infection is
further increased by the prevalence of morbid obesity in the
recipient population (Dick et al, 2009).
Diagnosis of infection can be complicated by a relative
absence of symptoms, as infection frequently manifests only as
a leukocytosis (Reid et al, 2009). As part of the pretransplanta-
tion evaluation, recipients should undergo an infectious disease
workup and should receive appropriate vaccines. Appropriate
antimicrobial prophylaxis can reduce the postoperative infec-
tion rate by more than half, depending on the pathogen. The
current prophylactic regimen used at Washington University in
St. Louis is shown in Box 98A.2.
Box 98A.2
Antimicrobial Prophylaxis for Liver Transplantation
Patients at Washington University in St. Louis
Bacterial
Routine use of broad-spectrum antibiotics on-call to operating room,
continued for 24 h postoperatively
Fungal
Fluconazole (Diflucan, once weekly) for 3 mo postoperatively in high-risk
patients
Pneumocystis Carinii
Trimethoprim-sulfamethoxasole (Bactrim/Septra SS) for 1 yr
postoperatively
Pentamidine (Pentam) or dapsone for patients with sulfa sensitivity
Viral
High Risk
Donor CMV+/recipient CMV−: valganciclovir 900 mg daily for 3 mo, then
450 mg daily for 9 mo
Intermediate Risk
(D+/R+ or D−/R+): Valganciclovir 450 mg daily for 6 mo
Low risk (D−/R−): acyclovir 200 mg bid for 3 mo
CMV, cytomegalovirus
Bacterial pathogens are the most common infectious agent
in the early postoperative period, and the proportion of post-
transplantation infection as a result of bacteremia has increased
significantly (Singh et al, 2004). DM and serum albumin less
than 3 mg/dL are independent risk factors for bacteremia.
Although gram-negative bacilli remain frequent causes of
postoperative infection after OLT, gram-positive cocci, such
as methicillin-resistant Staphylcoccus aureus (MRSA) and
vancomycin-resistant enterococci (VRE), have become increas-
ingly prevalent at many transplant centers (Papanicolaou et al,
1996; Reid et al, 2009; Singh et al, 2004). Colonization with
MRSA and VRE before transplantation increases the risk of
developing infection after OLT with the same organism and, in
the case of VRE colonization, is associated with an increased
mortality risk (Russell et al, 2008).
Typically presenting in the first 2 to 3 weeks after transplan-
tation, 25% of OLT patients are reported to develop MRSA
bacteremia, with colonization of indwelling vascular catheters
accounting for about half of the cases (Singh et al, 2000a). Vas-
cular catheters account for one quarter of bacteremia for all
pathogens combined. Other sources of post-OLT bacteremia
include—in decreasing order of frequency—pneumonia, biliary
infections, abdominal sources, and surgical wound infections
(Singh et al, 2000b, 2004). The emergence of drug-resistant
organisms resulting from overuse of common antibiotics has
made the treatment of infected liver transplant recipients
increasingly difficult.
CMV is the most common viral pathogen encountered by
OLT recipients, although incidence of CMV infection has
declined as a result of improved prophylaxis (Singh et al, 2004).
Intraoperative hypothermia is a known risk factor for develop-
ing CMV infection regardless of prophylaxis (Paterson et al,
1999). Without appropriate prophylaxis, the overall incidence
in this population is commonly 50% to 60%, with clinically
apparent infections usually occurring 3 to 12 weeks after trans-
plant (Farmer et al, 2000).
The routine use of ganciclovir (Cytovene) has been shown
to dramatically reduce CMV infection after OLT in several
randomized, controlled trials (Gane et al, 1997; Winston, 1995;
Winston & Busuttil, 2003, 2004). The standard regimen
includes an induction with intravenous ganciclovir followed by
prophylaxis with oral ganciclovir for 3 to 6 months. Some
studies suggest that valganciclovir, which can be administered
with once-daily dosing because of improved bioavailability,
might be as efficacious and safe as ganciclovir in the prevention
of CMV infection in low-risk, but not high-risk, liver recipients
(Jain et al, 2005; Park et al, 2006; Shiley et al, 2009); pro-
longed treatment (≥100 days) can be costly and might be
unnecessary in low-risk patients (e.g., seronegative donor and
recipient). Ganciclovir-resistant CMV has been observed in
20% of solid-organ transplant recipients treated with ganciclo-
vir, with presentation typically observed late in the first year
(Limaye et al, 2000). Our current strategy is to reserve pro-
longed treatment with ganciclovir for seronegative patients
receiving a seropositive graft or in patients with evidence of
active CMV infection.
Invasive fungal infections usually are caused by Candida or
Aspergillus species, Cryptococcus, and non-Aspergillus mycelial
fungi, with an incidence of 5% to 9% in OLT patients (Pappas
et al, 2010; Singh, 2000). Invasive candidiasis and aspergillosis
tend to occur relatively early in the postoperative period,
whereas Cryptococcus infection becomes apparent several
 SECTION III TECHNIQUES Chapter 98A Orthotopic Liver Transplantation
months to years after OLT (Pappas et al, 2010). Traditionally,
Candida albicans has been the most common fungal pathogen.
Risk factors for developing fungemia include use of broad-
spectrum antibiotics or immunosuppressant medications,
retransplantation or other reoperative intervention, CMV infec-
tion, renal failure, and overall severity of medical illness
(Cruciani et al, 2006). Routine prophylaxis with antifungal
agents—such as fluconazole, itraconazole, and amphotericin
B—significantly reduces fungal infection and infection-related
mortality after liver transplantation; however, it does not
improve overall mortality (Cruciani et al, 2006). Historically,
fluconazole was almost universally included in antimicrobial
prophylaxis, but this subsequently led to an increase in reported
Aspergillus infections, because Aspergillus is not susceptible to
fluconazole.
Currently, a majority of transplant centers provide anti-
fungal prophylaxis only to high-risk patients, including those
requiring retransplantation or reexploration, dialysis, mechani-
cal ventilation, or a prolonged ICU stay and those subject to
and graft failure or colonization with Candida (Singh et al,
2008). Although prophylaxis against Aspergillus is not supported
by the literature (Braun et al, 1998; Singh 2000), voriconazole,
amphotericin B, and caspofungin may be used alone or in com-
bination for treatment of invasive aspergillosis (Singh et al,
2008), which is associated with a 40% 1 year mortality rate after
infection (Pappas et al, 2010).
Infection with the protozoan Pneumocystis carinii occurs in
3% to 11% of liver transplant patients in the absence of prophy-
laxis (Singh, 2000). Because T-cell immunity is the primary
defense against this organism, prolonged use of corticosteroids
or muromonab-CD3 monoclonal antibodies and active CMV
infection increase the risk of infection. Trimethoprim-
sulfamethoxazole (single strength, once daily) offers highly
effective prophylaxis at a low cost and with minimal side effects.
Because the risk of P. carinii infection is eightfold higher in the
first year after OLT than in subsequent years, prophylaxis gen-
erally is continued only during these initial 12 months (Gordon
et al, 1999).
Rejection
Rejection can sometimes be a major hurdle to long-term sur-
vival after OLT. Previously reported to occur in 40% to 70%
of OLT patients (Klintmalm, 1991), the development of novel
immunosuppressive regimens has reduced the lifetime rejection
rate to less than 20% (McAlister et al, 2001). It is becoming
increasingly clear that certain subpopulations of patients receiv-
ing OLT can be weaned completely from all immunosuppres-
sive agents without experiencing rejection (Devlin et al, 1998;
Mazariegos et al, 1997). The University of Pittsburgh experi-
ence shows that immunosuppression can be withdrawn success-
fully in almost one third of patients, although it is unknown
exactly what traits allow such weaning.
Hyperacute rejection is rarely seen today. It typically occurs
in the setting of ABO incompatibility, with a reported graft
failure rate of 46% observed in 51 patients transplanted across
ABO type (Demetris et al, 1988). Hyperacute rejection is medi-
ated by preformed antibodies in the recipient and is directed
against the graft endothelium. These antibodies produce activa-
tion of the innate immune system via the complement cascade,
ultimately leading to rapid graft destruction. Retransplantation
is the only treatment option.
1731
Although acute liver rejection usually occurs within the first
4 weeks after transplantation, it can occur later. Patients with
acute liver rejection are seen with signs of fever, malaise, right
upper quadrant abdominal pain, and elevated liver transami-
nases. Elevation in liver enzymes is often detected before physi-
cal symptoms or signs occur. Percutaneous liver biopsy reveals
portal inflammation with predominantly mononuclear cells,
bile duct inflammation and injury, centrilobular necrosis, and
lobular inflammation. Differentiation from other pathologic
processes can be difficult. In contrast to other solid-organ trans-
plants, such as kidney and heart, the occurrence of an acute
rejection episode does not seem to reduce the overall graft sur-
vival, if treatment is initiated promptly (Wiesner et al, 1998).
The treatment for acute rejection is usually bolus corticoste-
roids: 1000 mg methylprednisolone (Solu-Medrol), followed by
a 5-day taper. Patients who do not respond to bolus steroids
may require additional strategies, including the use of mono-
clonal anti–T-cell antibody therapy (e.g., OKT3); however, this
is rarely needed in the current era because fewer than 5% of
patients experience rejection. When patients fail to respond to
bolus steroid therapy, it is important to be certain of the diagno-
sis and to consider other potential causes of abnormal liver
tests, including biliary or vascular causes. Repeat biopsies can
be helpful to confirm the diagnosis and assess the response to
therapy.
Today, only about 2% of patients experience chronic rejec-
tion after liver transplantation, although the incidence is higher
in patients with autoimmune disease (Wiesner et al, 2003). The
etiology of chronic rejection is multifactorial, characterized by
progressive loss of bile ducts, obliteration of medium-sized and
large hepatic arterioles, and cellular portal infiltration (Farmer
et al, 2000). Standardized histopathologic evaluation of acute
and chronic rejection using the Banff schema (Tables 98A.3
and 98A.4) allows objective decision making and facilitates
comparisons of natural histories among patients (Banff Con-
sensus, 1997; Demetris et al, 2000; Racusen et al, 2003).
Metabolic and Systemic Complications
With the increase in overall survival after OLT, a growing recog-
nition has emerged of associated long-term medical sequelae
and their impact on patient health. Prolonged use of corticoste-
roids can produce hyperlipidemia, obesity, DM, arterial hyper-
tension, and mineral-deficient bone disease; commonly used
antirejection drugs induce similar derangements. Cardiovascu-
lar disease then becomes a leading cause of death in patients
who survive more than 3 years after liver transplantation,
accounting for more than half of the reported mortality in some
series (Asfar et al, 1996; Pruthi et al, 2001). Predictors of peri-
operative cardiac events include pre-OLT history of stroke,
and perioperative mortality was increased with a history of
coronary artery disease (CAD) and postoperative sepsis (Safadi
et al, 2009).
Renal Dysfunction
Liver transplant recipients have a high risk of developing post-
transplant chronic renal failure, with an incidence of 18% at 5
years (Ojo et al, 2003). The average functional decline in renal
function is a 38% decrease in glomerular filtration rate, and it
is correlated with time elapsed since transplantation (decline
by 36 mL/min/1.73m2) (Bucuvalas et al, 2006; Karie-Guigues
1732 PART 8 LIVER AND PANCREAS TRANSPLANTATION Section III Techniques

Table 98A.3
Rejection Activity Index from the Banff Schema for Acute Hepatic Rejection
Category Criteria Score
Portal inflammation Mostly lymphatic inflammation involving a minority of the triads 1
Expansion of most triads by a mixed infiltrate containing lymphocytes, neutrophils, and eosinophils 2
Marked expansion of most or all triads by a mixed infiltrate containing numerous blasts, with spillover into 3
periportal parenchyma
Bile duct damage Minority of ducts infiltrated by inflammatory cells, with only mild reactive changes in epithelial cells 1
Most or all ducts infiltrated by inflammatory cells, with occasional degenerative duct changes, such as nuclear 2
pleomorphism, disorder polarity, and vacuolization
As above, with most or all ducts showing degenerative changes 3
Venous endothelial Subendothelial lymphocytic infiltration of some portal or hepatic venules 1
inflammation Subendothelial infiltration involving most or all portal or hepatic venules 2
As above, with perivenular inflammation extending into surrounding parenchyma and associated hepatocyte necrosis 3
This index has a range from 0 to 9, classified as follows: 0 to 3, minimal acute rejection; 4 to 6, mild acute rejection; 7 to 9, moderate to severe acute rejection.
Modified from the Banff Consensus, 1997: schema for grading liver allograft rejection: an international consensus document. Hepatology 25:658-663.

et al, 2009). The use of calcineurin inhibitors (CNIs) is associ-
ated with increased risk of renal failure in patients after OLT,
although this decline may be partially attenuated with concomi-
tant administration of mycophenolate mofetil and calcineurin
dose reduction (Karie-Guigues et al, 2009). Other risk factors
for the onset of post-OLT renal dysfunction include age and
gender of the recipient, history of HCV infection, DM, and pre-
transplantation renal insufficiency, CAD, and primary nonfunc-
tion (Ojo et al, 2003; Pawarode et al, 2003). Mortality following
OLT is four times greater in recipients who develop posttrans-
plantation renal failure (Ojo et al, 2003).
2009). Posttransplantation obesity develops in 60% of patients,
with most excess weight gain occurring in the first year (Muñoz
et al, 1991). The cause of weight gain is multifactorial: cortico-
steroids and cyclosporine, and to a lesser extent tacrolimus, are
known to correlate significantly with the incidence of obesity
(Canzanello et al, 1997). Development of PTMS does not seem
to be influenced by the etiology of the recipient’s ESLD (Bianchi
et al, 2008); however, liver transplant recipients who develop
PTMS appear to be at higher risk for vascular events (Laryea
et al, 2007) and are at higher risk for development of allograft
steatosis (Dumortier et al, 2010).

Posttransplantation Metabolic Syndrome Diabetes Mellitus

Posttransplantation metabolic syndrome (PTMS) is becoming
recognized as an important entity in liver transplant recipients.
Prevalence in the post-OLT population is twice that of the esti-
mated 24% prevalence in the general population (Bianchi et al,
2008; Hanouneh et al, 2008; Laryea et al, 2007; Pagadala et al,
De novo DM occurs in up to one third of previously nondia-
betic liver transplant recipients (Navasa et al, 1996; Sheiner
et al, 2000). Corticosteroids are known to induce insulin resis-
tance, and the occurrence of graft rejection necessitating
increased steroid dosing is a risk factor for developing diabetes.

Table 98A.4
Banff Schema for Chronic Hepatic Rejection
Structure Early Chronic Rejection Late Chronic Rejection
Small bile ducts (<60 μm) Degenerative changes involving most ducts: increased Degenerative changes in remaining bile ducts
nuclear-to-cytoplasmic ratio, nuclear hyperchromasia,
uneven nuclear spacing, ducts partially lined with epithelium
Bile duct loss in <50% of portal tracts Bile duct loss in >50% of portal tracts
Terminal hepatic venules Intimal/luminal inflammation Focal obliteration
Lytic zone 3 necrosis and inflammation Variable inflammation
Mild perivenular fibrosis Severe (bridging) fibrosis
Portal tract hepatic arterioles Occasional loss involving <25% of portal tracts Loss involving >25% of portal tracts
Large perihilar hepatic artery Intimal inflammation, focal foam-cell deposition Luminal narrowing by subintimal foam cells and
branches fibrointimal proliferation
Large perihilar bile ducts Inflammation damage, focal foam-cell deposition Mural fibrosis
Other “Transition” hepatitis with spotty necrosis of hepatocytes Sinusoidal foam cell accumulation, marked cholestasis
Modified from Demetris A, et al, 2000: Update of the International Banff Schema for Liver Allograft Rejection: working recommendations for the histopathologic staging and
reporting of chronic rejection: an international panel. Hepatology 31:792-799.
 SECTION III TECHNIQUES Chapter 98A Orthotopic Liver Transplantation
Tacrolimus and other immunosuppressants also increase insulin
resistance. Diabetes in most patients is transient and generally
resolves within the first year, as immunosuppressive medica-
tions are tapered.
Infection with HCV is another known risk factor for the
development of posttransplantation diabetes, and this risk is
correlated with increased HCV viral load (Delgado-Borrego
et al, 2008). Although the mechanisms underlying the relation-
ship between HCV and diabetes are not fully understood,
altered insulin sensitivity is likely to play a role. Pretransplanta-
tion glucose intolerance, as determined by formal glucose chal-
lenge testing, is present in 53% of candidates awaiting liver
transplantation (Blanco et al, 2001). Although some degree of
glucose intolerance may improve with OLT, insulin-dependent
diabetes almost never resolves after transplantation (Shields
et al, 1999; Stegall et al, 1995). Additionally, insulin-dependent
DM is a known risk factor for lower survival following trans-
plantation, and CAD is an independent predictor of worse out-
comes (Yoo & Thuluvath, 2002).
Neurologic Complications
Neurologic complications occur with greater frequency in
recipients of liver allografts than in other solid-organ recipients
(Senzolo et al, 2009). The aggregate prevalence of neurologic
sequelae is 25%, although such have occurred in more than
60% of patients in some series (Amodio et al, 2007; Bronster
et al, 2000; Emiroglu et al, 2006; Ghaus et al, 2001; Lewis &
Howdle, 2003; Saner et al, 2006).
Posttransplantation encephalopathy is the most common
neurologic complication, followed by seizures (Bronster et al,
2000; Lewis & Howdle, 2003; Saner et al, 2006; Senzolo et al,
2009). Encephalopathy can be caused by anoxia, sepsis, medi-
cations (especially CNIs), primary graft nonfunction, renal
failure, rejection, and central pontine myelinolysis (CPM) (Erol
et al, 2007). Infection, stroke, and CPM are also common
causes of seizures (Senzolo et al, 2009). Other neurologic com-
plications include posterior leukoencephalopathy, cerebellar
syndrome, focal deficits, headache, tremor, sleep disorders, and
peripheral neuropathy. Risk factors for neurologic complica-
tions include an operative time longer than 10 hours, high CTP
score, and a history of hepatic encephalopathy (Dhar et al,
2008). Older age and higher MELD scores pretransplantation
are associated with increased risk of tacrolimus-related neuro-
toxicity (DiMartini et al, 2008). In cases of CNI-related neuro-
toxicity, patients can frequently be switched to a different drug
within the same class with successful resolution of symptoms
(Emiroglu et al, 2006; Erol et al, 2007). Most central nervous
system (CNS) complications (80%) occur within 1 month after
OLT but may be seen up to several years after transplantation
(Bronster et al, 2000). The incidence of neurologic complica-
tions in LDLT recipients (17%) approximates that of cadaveric
allograft recipients, and outcomes from these complications
appear to be similar (Saner et al, 2010).
Immunosuppressant Toxicity
CNIs can cause significant renal and neurotoxicity. Use of siro-
limus as an alternative immunosuppressant in patients with
these adverse effects may allow patients to recover from CNI
toxicity without significant risk of rejection (Di Benedetto et al,
2008; Morard et al, 2007).
1733
OUTCOMES
Survival after OLT has improved markedly as a result of con-
tinuing refinements in organ procurement and preservation,
recipient selection, surgical and anesthetic techniques, periop-
erative care, and long-term immunosuppression. Overall patient
survival at 10 years is 60% in the United States, with an unad-
justed 10-year graft survival of 54% (Thuluvath et al, 2010).
In select patient populations, some institutions have achieved
near zero short-term mortality (Broering et al, 2004; Sugawara
et al, 2002).
Recipient factors associated with reduced survival include
recipient age over 65 years, preexisting CAD, insulin-dependent
DM, renal insufficiency, and extreme body mass index (BMI)
(Busuttil et al, 2005; Dick et al, 2009; Nair et al, 2002; Thulu-
vath et al, 2010; Yoo & Thuluvath, 2002). Other factors that
adversely affect survival include conditions that require urgent
transplantation, such as hepatic malignancy as the indication
for transplantation, donor hospitalization longer than 6 days,
cerebrovascular accident as donor cause of death, prolonged
warm (>45 minutes) and cold (>10 hours) ischemic time, and
retransplantation (Busuttil et al, 2005).
Deceased-donor split allografts have not been shown to
adversely affect outcomes in large series (Busuttil et al, 2005),
and LDLT over the last decade has had better long-term out-
comes than deceased-donor transplantation (Thuluvath et al,
2010). The overall rate of retransplantation for recipients of
DDLT was 7.8% in 2007, representing the lowest level in the
last decade (USRTR, 2008). Outcomes after liver transplanta-
tion for certain disease processes are discussed below.
Biliary Atresia
The long-term primary hepatic salvage rate after portoen-
terostomy in infants with biliary atresia ranges from 20% to
45% (Davenport et al, 2004; Otte et al, 1994; Schreiber et al,
2007; see Chapter 40). The remaining infants develop progres-
sive biliary cirrhosis and ultimately require liver transplanta-
tion. Biliary atresia is the most common indication for OLT
in children younger than 18 years, and the best results are
obtained in patients referred for transplantation early, after
only a single attempted portoenterostomy. Approximately 80%
of children transplanted for biliary atresia have had a prior
biliary drainage procedure (Utterson et al, 2005; Visser et al,
2004). Despite this high rate of transplantation, portoenteros-
tomy remains a viable bridge to definitive therapy, allowing
infants to grow.
Transplantation is a durable solution for biliary atresia, and
this recipient population obtains the best survival rates, with
10-year patient survival greater than 80% and graft survival
greater than 67% (Barshes et al, 2005; D’Alessandro et al,
2007; Diem et al, 2003; Farmer et al, 2007; Schreiber et al,
2007; Visser et al, 2004). The use of split-liver cadaveric grafts
and living related transplantation has expanded the potential
donor pool, extending OLT to an increased number of children
with biliary atresia, without a significant increase in post-
OLT mortality (Barshes et al, 2005; Chen et al, 2006; Yersiz
et al, 2003).
Additionally, use of living-donor liver allografts significantly
shortens time on the waiting list (Visser et al, 2004); however,
technical variant grafts may increase the risk of graft failure
(Utterson et al, 2005). Graft failure and vascular complications
1734 PART 8 LIVER AND PANCREAS TRANSPLANTATION Section III Techniques
account for the majority of early post-OLT deaths, whereas
rejection remains the leading cause of late death in these patients
(Barshes et al, 2005).
Primary Sclerosing Cholangitis
and Primary Biliary Cirrhosis
Primary sclerosing cholangitis (PSC) is a chronic cholestatic
liver disease of unknown origin that is frequently associated
(70% to 80%) with inflammatory bowel disease, usually ulcer-
ative colitis (UC; see Chapter 41). Patients with PSC also are
at risk for the development of cholangiocarcinoma. Although
medical palliation exists, the only cure for PSC is liver trans-
plantation. Outcomes after OLT for PSC are excellent, with
5-year patient survival rates ranging from 80% to 85% (Goss
et al, 1997; Ricci et al, 1997; Solano et al, 2003) and 10-year
survival at 70% (Busuttil et al, 2005). Whether the incidental
discovery of cholangiocarcinoma in the explanted liver affects
patient survival is controversial (Goss et al, 1997; Solano et al,
2003). Approximately 9% to 11% of patients develop recurrent
PSC after transplantation.
Primary biliary cirrhosis (PBC) is an autoimmune disease
typically characterized by the development of circulating anti-
mitochondrial antibodies (AMAs). Patients with PBC generally
have better long-term survival (>7 years) than patients trans-
planted for PSC (Maheshwari et al, 2004). They are more
prone to chronic rejection, however, and are less likely to be
weaned from immunosuppression (MacQuillan et al, 2003).
PBC likely recurs in a few patients after OLT, although long-
term follow-up data are lacking, and this rate appears to be
much less common than for PSC recurrence. Posttransplantation
AMA titers are not predictive of disease recurrence; a liver
biopsy specimen showing granulomatous destructive cholangi-
tis remains the gold standard (Faust, 2001).
Alcoholic Cirrhosis
Although often producing ESLD in conjunction with viral hep-
atitis, alcoholic cirrhosis is one of the leading indications for
OLT in the United States (Amersi et al, 1998; Thuluvath et al,
2010). Early reports showing equivalent outcomes in patients
with alcoholic cirrhosis compared with patients with nonalco-
holic cirrhosis resulted in widespread application of OLT for
this indication (Bird et al, 1990; Starzl et al, 1988). Medical
outcomes in this group continue to be good (Busuttil et al,
2005; DiMartini et al, 1998; Lim & Keeffe, 2004).
Recidivism occurs in roughly 20% to 30% of patients trans-
planted for alcoholic cirrhosis (Biselli et al, 2010; Pageaux et al,
2003; Rowley et al, 2010). Although there is little convincing
evidence that resumption of drinking adversely affects graft or
patient survival after OLT, there are ethical concerns over pos-
sibly misallocating donor organs to active substance abusers
(Lim & Keeffe, 2004). Relapse might also serve as a proxy
marker for patients who are likely to have poor nutrition and
overall health as well as poor compliance with their immuno-
suppressive regimen and, therefore, increased risk of rejection
(Pageaux et al, 2003). Most transplant centers require potential
transplant candidates to participate in a support program,
undergo psychologic evaluation, and remain abstinent from
substance abuse, with documented random drug and alcohol
testing for at least 6 months before placement on the waiting
list. Multivariate analysis of alcoholic patients with cirrhosis
who have undergone OLT showed that abstinence for 6 months
or more before OLT is the strongest predictor for nonrelapse
after transplantation (Miguet et al, 2004).
Hepatitis B Virus
Since the standardization of HBV treatment with hepatitis B
immunoglobulin (HBIG) and antiviral agents, the rate of recur-
rent HBV infection in liver transplant recipients has declined
from 80% in untreated patients to less than 10% of treated
patients at 2 years (Roche & Samuel, 2004; Saab et al, 2009;
Todo et al, 1991; see Chapter 64). Current treatment strategies
include reducing or eliminating active viral replication before
transplantation through the administration of lamivudine or
adefovir, in combination with other agents, then combining one
of these with HBIG after OLT indefinitely. This approach has
resulted in similar outcomes for patients without recurrence
compared with patients undergoing OLT for other reasons
(Kim et al, 2004; Roche et al, 2003; Steinmuller et al, 2002);
however, HBIG administration can be costly and cumbersome,
and resistance to lamivudine is reported in 20% of patients after
treatment for 1 year.
Although combination prophylaxis with lamivudine and
HBIG is highly effective, other methods to combat HBV recur-
rence are being investigated. Alternative regimens include com-
bination antiviral agents (e.g., lamivudine and adefovir) without
routine use of HBIG (Nath et al, 2006). HBV recurrence por-
tends a poor outcome, with a 5-year survival rate of 47% (Saab
et al, 2009). For patients with HCC at transplantation, recur-
rent HBV infection is also significantly associated with a recur-
rence of HCC after transplantation (Saab et al, 2009).
Hepatitis C Virus
Since its definitive identification in 1989, HCV has been deter-
mined to be a major cause of chronic liver disease and cirrhosis,
accounting for 37% to 41% of OLT performed in the United
States (Thuluvath et al, 2010). Approximately 2% of the general
population carries the virus, and 50% to 60% of these indi-
viduals develop chronic liver disease (Farmer et al, 2000; see
Chapter 64).
Short-term and intermediate-term patient survival after
OLT for HCV is not significantly different from HCV-negative
patients who receive transplants for other nonmalignant
reasons, although graft survival is significantly reduced com-
pared with allografts for alcoholic liver disease (Biselli et al,
2010; Boker et al, 1997; Ghobrial et al, 2001). Unadjusted
10-year survival rates are lower for HCV-positive recipients in
the United States (Thuluvath et al, 2010). Recurrent infection
is nearly universal, and chronic hepatitis develops in most
patients after OLT (Gordon et al, 2009). The clinical course is
similar to nontransplanted HCV-positive patients, with only
13% developing hepatic fibrosis (Saab et al, 2009). In these
patients with recurrent hepatitis C cirrhosis, 5-year survival
decreases to 30% (Saab et al, 2005). Recipients coinfected with
HIV tend to experience faster and more aggressive recurrence
of HCV (Di Benedetto et al, 2008).
In contrast to HBV, no approved therapies are currently
available for prevention of recurrent HCV infection after liver
transplantation. Outcomes for transplantation of HCV recipi-
ents with extended-criteria livers are significantly worse, and
donor age has been reported to affect graft survival adversely
 SECTION III TECHNIQUES Chapter 98A Orthotopic Liver Transplantation
(Lake et al, 2005; Machicao et al, 2004; Russo et al, 2004;
Thuluvath et al, 2010); however, older donors can be safely
used, with similar results in HCV-positive recipients with short
cold and warm ischemia times and careful donor selection
(Doyle et al, 2008).
Hepatocellular Carcinoma
(See Chapters 80 and 97D)
HCC was one of the first documented indications for OLT
(Starzl et al, 1968). The decision to utilize transplantation for
this disease is based on the oncologic premise of performing
a complete resection (total hepatectomy) with wide surgical
margins to effect a cure and to remove potential future sites
of tumor formation in the diseased remnant liver. Improved
selection of appropriate candidates with HCC for OLT has
led to improved outcomes and consequently has more than
doubled the number of patients with HCC on the waiting list
(Thuluvath et al, 2010).
Liver transplantation in the setting of extrahepatic malig-
nancy is contraindicated. Conversely, the finding of incidental
HCC in the explanted specimen after transplantation for a non-
malignant indication does not alter patient or graft outcome
significantly (Cillo et al, 2004). The difficulty has been the
selection of patients for OLT with malignant disease confined
to the liver but at an advanced stage.
In their series examining liver transplantation for HCC,
Mazzaferro and colleagues (1996) obtained a 75% 4-year actu-
arial survival using specific guidelines in highly selected patients.
Subsequently termed the Milan criteria for OLT, patients under
this protocol were offered transplantation if they had a solitary
tumor less than 5 cm in diameter or no more than three nodules,
each less than 3 cm in diameter (stage II). Largely as a result of
this report, UNOS adopted these criteria for placing potential
recipients on the waiting list, limiting transplantation to patients
with stage I (single tumor up to 2 cm in diameter) or stage II
disease.
Currently, MELD exception points (22 points) are awarded
only on a routine basis to patients with stage II HCC, who
account for 8% to 9% of all deceased-donor liver recipients
today (USRTR, 2008). Patients with more advanced HCC can
only receive additional MELD priority points through special
appeal to regional review boards of transplant surgeons and
physicians. Although not equaling the excellent results of
Mazzaferro and colleagues (1996), reported 5-year survival
after OLT for HCC generally ranges from 60% to 75% in
several large, more recent series (Goodman et al, 2005; Yao
et al, 2001; Yoo et al, 2003).
Several centers have attempted to expand liver transplanta-
tion to patients with tumors exceeding the Milan criteria and
have met with varying degrees of success. The University of
California–San Francisco (UCSF) criteria permit transplanta-
tion for patients with solitary tumors smaller than 6.5 cm diam-
eter, fewer than three tumors, and a maximum diameter less
than 4.5 cm or total cumulative diameter less than 8 cm (Yao
et al, 2001).
Prospective trials currently are examining multimodal treat-
ment for HCC, whereby patients undergo chemoembolization
or other ablative techniques to downstage the tumor clinically,
followed by transplantation. We require patients with stage III
or IV HCC to undergo tumor downstaging, usually with TACE,
to meet Milan criteria and with a minimum period of 3 months
1735
of observation without evidence of extrahepatic tumor on
restaging. Our results using this strategy in highly selected
patients are equivalent to patients initially meeting Milan crite-
ria without the need for downstaging (Chapman et al, 2008).
Currently, 58% of patients receiving MELD exception points
for HCC have undergone TACE or radiofrequency ablation
while on the waiting list, with the majority receiving TACE
(Thuluvath et al, 2010). Although no prospective trials demon-
strate a long-term oncologic benefit to pretransplantation
TACE, retrospective data strongly suggest that this may be ben-
eficial, and we consider this a routine practice in our HCC
transplant candidates (Bharat et al, 2006).
Cholangiocarcinoma
(See Chapters 50C and 97E)
No effective medical treatment has been found for cholangio-
carcinoma. Surgical extirpation is feasible in less than 30% of
all patients and produces 5-year survival rates less than 30%,
even with complete resection (Jarnagin et al, 2001; Rea et al,
2004). Additionally, patients with PSC, a known risk factor for
cholangiocarcinoma, are often poor candidates for resection
because of concurrent cirrhosis. Historically, the use of OLT
for treatment of cholangiocarcinoma has been associated with
5-year survival rates of 30% and even lower rates in patients
with incidentally discovered cholangiocarcinoma at trans-
plantation (Becker et al, 2008). Surgeons at the Mayo Clinic
reported successful results using strict treatment protocols
for performing OLT in patients with localized, node-negative
hilar cholangiocarcinoma, which included the use of neoadju-
vant chemoradiation, staging laparotomy, resection to negative
margins, and OLT (see Chapter 97E). Using these or similar
protocols, 5-year survival rates of 72% have been achieved in a
highly selected group of patients, many of whom had PSC
(Heimbach et al, 2004; Rea et al, 2009; Sudan et al, 2002). Ret-
rospective analysis revealed improved outcomes for patients
enrolled in the Mayo protocol compared with those of patients
undergoing major hepatic resection (Rea et al, 2005); however,
these outcomes have been difficult to achieve at other institu-
tions, and neoadjuvant therapy is associated with higher rates of
arterial and venous complications after transplantation (Mantel
et al, 2007).
Fulminant Hepatic Failure
(See Chapters 72 and 97C)
The cohort that undergoes OLT for fulminant hepatic failure
comprises a diverse group of patients and disease etiologies. By
definition, these patients have no previous demonstrable liver
disease, yet they present acutely with encephalopathy; synthetic
dysfunction, such as coagulopathy; and jaundice. Most com-
monly, the etiology is never determined, but fulminant hepatic
failure (FHF) can be caused by drugs, viruses, toxins, or other
liver injuries (Hoofnagle et al, 1995). Although artificial liver
support systems are under development, the only widely avail-
able cure for acute liver failure is OLT. Limited donor organ
availability leads to the relatively high waiting-list mortality
rate of 377 deaths per 1000 patient-years at risk. MELD scores
tend not to predict outcome accurately in patients with FHF
(Kremers et al, 2004); in this setting, outcome after OLT is
below average, with approximately 67% of patients surviving to
5 years (Farmer et al, 2003).
1736 PART 8 LIVER AND PANCREAS TRANSPLANTATION Section III Techniques
Nonalcoholic Steatohepatitis (See Chapter 65)
Cirrhosis secondary to nonalcoholic steatohepatitis (NASH) is
a rapidly increasing indication for liver transplantation, account-
ing for approximately 5% of transplantations performed in
2007 (USRTR, 2008). NASH, a stepwise progression in the
natural history of nonalcoholic fatty liver disease (NAFLD), is
associated with obesity. Data gathered to study the effects of
BMI on outcomes of OLT are inconclusive. Although it has
been shown that morbidly obese recipients are at higher risk for
PTMS and infectious complications, it has not been definitively
shown to affect long-term outcomes (Leonard et al, 2008;
Malik et al, 2009). Independent risk factors for development of
graft steatosis after OTL include pretransplantation graft ste-
atosis, post-OLT obesity, hypertension, DM, hyperlipidemia,
use of tacrolimus, and alcoholic cirrhosis as the primary indica-
tion for liver transplantation (Dumortier et al, 2010).
RETRANSPLANTATION
The rate of retransplantation has been gradually declining,
reaching a low of 7.8% in 2007 (USRTR, 2008). In particular,
the rate of retransplantation for HCV dropped to 5% in 2008
(Thuluvath et al, 2010). The most common indications for
retransplantation include primary nonfunction (46% of retrans-
plants), HAT (29%), acute and chronic rejection (7%), and
recurrent disease (Busuttil et al, 2005; Jain et al, 2000; Lang
et al, 2008; Marti et al, 2008; Thuluvath et al, 2010). Use of
DCD allografts is associated with a 13% retransplantation rate,
which has remained stable over the last decade (Thuluvath
et al, 2010).
Outcome after retransplantation is generally worse than
after initial OLT but is slowly improving, with a 10-year graft
survival up to 69% in some centers (Marti et al, 2008);
however, this varies significantly by primary indication (Adam
& Hoti, 2009; Thuluvath et al, 2010). Patients requiring
retransplantation are at increased risk for infection, HAT, and
acute renal failure (Uemura et al, 2007). Retransplantation for
primary nonfunction yields 54% to 60% patient survival at
5 years (Kemmer et al, 2007; Uemura et al, 2007). Recurrent
HCV is associated with worse outcomes following retransplan-
tation overall, and most centers avoid retransplantation for
this indication; however, a recent multicenter analysis demon-
strated similar 3-year survival rates in a highly select group
of patients with recurrent HCV compared with non-HCV
retransplant recipients (McCashland et al, 2007). Factors por-
tending a poor prognosis include preoperative mechanical ven-
tilation, HCV infection, elevated creatinine and bilirubin, and
prolonged donor cold ischemia (Markmann et al, 1999; Yoo
et al, 2003).
CONCLUSION
Results after OLT have improved over the past 3 decades,
although outcomes may be expected to plateau as further
improvements add only a marginal survival benefit to an already
refined surgical procedure. The reasons for the successful devel-
opment of hepatic transplantation are as follows:
1. Organized regional and national networks designed for the
early identification of potential organ donors and rapid pro-
curement in select candidates
2. Improved surgical and anesthetic techniques, allowing previ-
ous obstacles to OLT to be overcome (e.g., PVT, severe
coagulopathy)
3. Novel antirejection and antimicrobial agents, with increasing
emphasis on achieving minimal immunosuppression in the
shortest time possible
4. Increased vigilance for the occurrence of acute complica-
tions after OLT, with the development of rapid screening
tests for HAT, PVT, and primary nonfunction
As the only treatment option for thousands of patients, and
with the added benefit of being curative for most candidate
recipients, OLT will continue to be offered for the foreseeable
future. Methods for expanding the donor pool and the more
recent revisions to the allocation process may help to ease the
shortage of suitable hepatic grafts. Newer immunosuppressive
agents and further understanding of the role, or even the neces-
sity, of immunosuppression in some patients may decrease the
morbidity for patients after OLT.
References are available at expertconsult.com.