Recipient Selection

Common indications for OLT (see Chapter 97A) include portal hypertension as manifested by variceal bleeding, ascites, encephalopathy, hyperbilirubinemia, hepatic synthetic dysfunction, and lifestyle limitations. More than 70% of liver transplantations 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 increasingly common cause of liver cirrhosis, as the prevalence of 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 uniformly 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 contraindications. 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 contraindications to OLT are extensive mesenteric venous thrombosis, morbid obesity, psychiatric disorders uncontrolled by conventional means, absence of a suitable social support network, and extremes of age (Jain et al, 2000; Loinaz et al, 2002; Rustgi et al, 2004).

Increasingly, advances in surgical technique and medical supportive care are overcoming obstacles and comorbid conditions formerly considered absolute contraindications to transplantation, 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, evidence 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 antiretroviral 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 transplantation, 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 predicts 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 transplantation. 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 transplantation 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 subcommittees to examine new methods for allocation. The result was the universal adoption of the MELD criteria (Table 98A.2) as a measure of the potential recipient’s necessity for OLT. Concurrent revision of the pediatric liver allocation process produced the Pediatric End-Stage Liver Disease (PELD) model, which is discussed further in Chapter 98C. Per a policy change in 2005, PELD is applied to potential transplant recipients younger than 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 from chronic liver disease (Malinchoc et al, 2000; Wiesner et al, 2003a). It incorporates serum creatinine, bilirubin, and international normalized ratio (INR) as markers for risk of death; relies on objective and readily available blood tests; and practically eliminates time on the waiting list from consideration. Using MELD criteria, rates of death while awaiting OLT and removal from the waiting list for being too sick have decreased (Thuluvath et al, 2010). Median time to transplant in 2007 was 361 days.

As shown in Figure 98A.2, the use of MELD criteria for predicting mortality from ESLD results in an appropriate correlation between severity score and actuarial survival at 3 months. Survival benefit analysis of liver transplant recipients stratified by MELD score demonstrates that the risks involved in transplantation are equivalent or less than the risks associated with remaining a transplant candidate on the waiting list with a MELD score over 15 (Merion et al, 2005). The MELD-based allocation process is dynamic and amenable to subtle changes to reflect an evolving understanding of the diverse pathology and physiology seen in patients treated with OLT.

FIGURE 98A.2 Correlation between Model for End-Stage Liver Disease (MELD) and the pediatric MELD (PELD) score and patient mortality. SPLIT, Studies of Pediatric Liver Transplantation.

(Adapted from Freeman RB Jr, et al, 2002: The new liver allocation system: moving toward evidence-based transplantation policy. Liver Transpl 8:851-858.)

Special considerations for certain subsets of patients with liver disease are ongoing. Early in the initial evaluation of the MELD criteria, it was recognized that patients with HCC and early cirrhosis should be prioritized lower on the waiting list, when they could potentially benefit most from transplantation (e.g., HCC at an early tumor stage; see Chapter 97D). Conceivably, patients with HCC but low MELD scores could develop progressive disease, which would eliminate OLT as a treatment option. Since the most recent revisions to MELD, patients with stage II HCC currently are allocated 22 MELD priority points. Criteria for selecting HCC patients for transplantation are discussed further in this chapter, including those with more advanced stage disease. Guidelines also exist for awarding priority points for other conditions, such as hepatopulmonary syndrome, portopulmonary hypertension, hepatic artery thrombosis after liver transplant, pediatric hepatoblastoma, inborn errors of metabolism, familial amyloidosis, and primary oxaluria; however, the process is highly variable by region (USRTR, 2008).

Since 2002, the number of patients on the waiting list with exception points for any condition has more than doubled, with close to 900 on the list in 2008 (Thuluvath et al, 2010). Increasingly, stage I and II hilar cholangiocarcinoma is becoming an acceptable indication for OLT, and uniform criteria for obtaining MELD exception points have been proposed (Gores et al, 2006; see Chapter 97E). Eligible patients must be treated according to a specific protocol that requires neoadjuvant chemoradiation, followed by a staging laparotomy to confirm absence of N1 disease (Rea et al, 2005).

Donor Selection

Increased demand for donor organs, as depicted in Figure 98A.1, has resulted in the concomitant increase in the use of less than ideal donors. The theoretic ideal donor is an otherwise healthy, hemodynamically stable young person who suffers an irreversible cerebral insult that results in brain death; this situation is rarely realized. Although marginal donors are being used more frequently, absolute contraindications remain, including 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 contraindications (Wachs et al, 1995), although many centers consider 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 recipient groups, such as HCV-positive recipients, remain inconclusive (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 cadaveric (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 survivals 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 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.

Donor Hepatectomy

Management of a cadaveric organ donor begins preoperatively, immediately after identification of a candidate and after evaluation by trained transplant coordinators. After brain death, severe physiologic derangements can occur, and physiologic instability increases in proportion to the length of time between declaration 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 insipidus (DI), pulmonary edema and hypoxia, acidosis, and arrhythmias 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 catheter 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 previously (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 preclude 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 dividing the umbilical, falciform, and left triangular ligaments. Hepatic arterial anatomy is delineated by inspection of the gastrohepatic ligament and porta hepatis to identify aberrant arterial anatomy. A right medial visceral rotation, or Cattel-Brasch maneuver, is performed, by which the right colon and mesentery 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 cannulated 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, facilitated 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 technique 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. Preservation of this artery, if present, is essential.

Next, the portal vein is dissected and divided near the pancreas, although a modification is necessary if pancreas procurement 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. Attention 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 thrombus formation in the graft (Bernat et al, 2006). Apnea and cessation 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 withdrawal of support; these patients are not candidates for subsequent 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 challenging technical aspect of liver transplantation. Hepatectomy often is complicated by marked portal hypertension, coagulopathy, 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. Preoperative 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.

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 temporary portocaval shunting or venovenous bypass; both techniques allow decompression of the splanchnic circulation, which reduces bowel edema during the anhepatic phase. When venovenous 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 complexity and potential complications associated with the bypass process (e.g., thrombosis of the bypass circuit). We prefer portocaval 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 piggyback 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 proximally, 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 retrohepatic IVC intact and requires ligation and division of all retrohepatic caval branches (Tzakis et al, 1989). The advantage of this approach is that native caval flow is maintained, and venovenous bypass is not required; the disadvantage is that division of retrohepatic caval branches can be tedious and time consuming. The donor suprahepatic IVC is anastomosed to the confluence 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. Retrospective 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 following order: 1) suprahepatic IVC; 2) infrahepatic IVC, if a bicaval technique is used; 3) portal vein; and 4) hepatic artery. Alternatively, 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, 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 interrupted 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 frequently spatulated and are sewn from the outside and rotated to achieve the most precise anastomosis. The presence of aberrant hepatic arterial anatomy is encountered in 10% to 30% of grafts, and preservation of these vessels is essential for successful 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 originating from the infrarenal and supraceliac aorta has been described; both methods provide excellent inflow, and the choice is based on technical considerations and surgeon preference. The best choice of conduit is usually the donor iliac vessels. When donor vessels are unavailable or inadequate, prosthetic conduits can be used, typically polytetrafluoroethylene (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 choledochojejunostomy. 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 the size match of the donor and recipient common bile duct and the presence of preexisting biliary pathology. Choledochocholedochostomy is preferable, because after OLT, access to the biliary tree is easier and safer with ERCP than with percutaneous transhepatic cholangiography. Choledochojejunostomy is used when the above-mentioned technical goals cannot be realized. 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 recipient bile duct should be cleared of sludge and stones. Accommodation 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 choledochocholedochostomy and choledochojejunostomy anastomoses are accomplished 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.

Primary Nonfunction

Primary nonfunction is defined as early graft failure after OLT in the absence of identified technical complications. Clinical presentation varies, but patients typically are seen with alterations in mental status, diminished bile production, coagulopathy, markedly elevated transaminases, and metabolic acidosis. Multiorgan failure ensues, with oliguria and hypoxia occurring frequently. 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 functional 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 performed before implantation of any graft that appears marginal (D’Alessandro et al, 1991). As would be expected, the likelihood 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 different 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 significantly higher incidence of 8% to 10% in the pediatric population (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 reconstruction, 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, cholangitis, 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 revascularization may salvage the graft, although this is usually not possible.

Some reports suggest that endovascular procedures—intraarterial thrombolysis, percutaneous transluminal angioplasty, 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 postoperative duplex US.

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 cholangitis, although in some cases patients may be asymptomatic with no clinical consequences (Gunsar et al, 2003). Contributing 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 percutaneous biliary decompression, stenting, or even systemic anticoagulation. 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 recognized 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 complications. 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 incidence 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 reconstruction 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 fulminant hepatic failure from PVT, reexploration and attempted portal revascularization are performed. These patients sometimes 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 portocaval shunt (TIPS) in conjunction with thrombolytics (Ciccarelli 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 anastomotic site. Narrowing of the main portal vein diameter by more than 50%, presence of a poststenotic jet, or lack of visualized 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 posttransplantation 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 complication rates than choledochocholedochostomy (O’Connor et al, 1995); however, this remains a controversial topic in transplantation techniques. All patients found to have a biliary complication 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 nonanastomotic (ischemic cholangiopathy) (Balsells et al, 1995; Qian et al, 2004). Most anastomotic strictures are managed endoscopically with balloon dilation and stenting. Ischemic cholangiopathy 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 endoscopic 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 multidisciplinary 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 collections 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 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 complications 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 experience at least one serious infectious episode (Winston et al, 1995), despite ever-improving prophylactic regimens. Intraabdominal infections occur in 40% of recipients with a higher incidence in patients with other noninfectious surgical complications (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 transfusions, and have undergone lengthy and complex surgical procedures—all of which are risk factors for infectious complications. 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 pretransplantation evaluation, recipients should undergo an infectious disease workup and should receive appropriate vaccines. Appropriate antimicrobial prophylaxis can reduce the postoperative infection 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.

Bacterial pathogens are the most common infectious agent in the early postoperative period, and the proportion of posttransplantation 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 increasingly 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 transplantation, 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). Vascular 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 developing 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 transplant (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); prolonged 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 ganciclovir, with presentation typically observed late in the first year (Limaye et al, 2000). Our current strategy is to reserve prolonged 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 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 infection, 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 antifungal prophylaxis only to high-risk patients, including those requiring retransplantation or reexploration, dialysis, mechanical 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 combination 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 prophylaxis (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 generally is continued only during these initial 12 months (Gordon et al, 1999).

Rejection

Rejection can sometimes be a major hurdle to long-term survival 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 receiving OLT can be weaned completely from all immunosuppressive agents without experiencing rejection (Devlin et al, 1998; Mazariegos et al, 1997). The University of Pittsburgh experience shows that immunosuppression can be withdrawn successfully 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 mediated by preformed antibodies in the recipient and is directed against the graft endothelium. These antibodies produce activation of the innate immune system via the complement cascade, ultimately leading to rapid graft destruction. Retransplantation is the only treatment option.

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 transaminases. Elevation in liver enzymes is often detected before physical 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 transplants, such as kidney and heart, the occurrence of an acute rejection episode does not seem to reduce the overall graft survival, if treatment is initiated promptly (Wiesner et al, 1998).

The treatment for acute rejection is usually bolus corticosteroids: 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 monoclonal 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 diagnosis 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 rejection 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 Consensus, 1997; Demetris et al, 2000; Racusen et al, 2003).

Table 98A.3 Rejection Activity Index from the Banff Schema for Acute Hepatic Rejection

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.

Table 98A.4 Banff Schema for Chronic Hepatic Rejection

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.

Metabolic and Systemic Complications

With the increase in overall survival after OLT, a growing recognition has emerged of associated long-term medical sequelae and their impact on patient health. Prolonged use of corticosteroids can produce hyperlipidemia, obesity, DM, arterial hypertension, and mineral-deficient bone disease; commonly used antirejection drugs induce similar derangements. Cardiovascular 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 perioperative 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 posttransplant 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 et al, 2009). The use of calcineurin inhibitors (CNIs) is associated with increased risk of renal failure in patients after OLT, although this decline may be partially attenuated with concomitant 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 pretransplantation renal insufficiency, CAD, and primary nonfunction (Ojo et al, 2003; Pawarode et al, 2003). Mortality following OLT is four times greater in recipients who develop posttransplantation renal failure (Ojo et al, 2003).

Posttransplantation Metabolic Syndrome

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 estimated 24% prevalence in the general population (Bianchi et al, 2008; Hanouneh et al, 2008; Laryea et al, 2007; Pagadala et al, 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: corticosteroids 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).

Diabetes Mellitus

De novo DM occurs in up to one third of previously nondiabetic liver transplant recipients (Navasa et al, 1996; Sheiner et al, 2000). Corticosteroids are known to induce insulin resistance, and the occurrence of graft rejection necessitating increased steroid dosing is a risk factor for developing diabetes. Tacrolimus and other immunosuppressants also increase insulin resistance. Diabetes in most patients is transient and generally resolves within the first year, as immunosuppressive medications 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 relationship between HCV and diabetes are not fully understood, altered insulin sensitivity is likely to play a role. Pretransplantation glucose intolerance, as determined by formal glucose challenge 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 transplantation, and CAD is an independent predictor of worse outcomes (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, medications (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 complications include posterior leukoencephalopathy, cerebellar syndrome, focal deficits, headache, tremor, sleep disorders, and peripheral neuropathy. Risk factors for neurologic complications 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 neurotoxicity (DiMartini et al, 2008). In cases of CNI-related neurotoxicity, 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 complications 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 sirolimus 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).

Biliary Atresia

The long-term primary hepatic salvage rate after portoenterostomy 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 progressive biliary cirrhosis and ultimately require liver transplantation. 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, portoenterostomy 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 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 ulcerative 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 transplantation. 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 antimitochondrial antibodies (AMAs). Patients with PBC generally have better long-term survival (>7 years) than patients transplanted 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 cholangitis remains the gold standard (Faust, 2001).

Alcoholic Cirrhosis

Although often producing ESLD in conjunction with viral hepatitis, 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 nonalcoholic 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 transplanted 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 possibly 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 immunosuppressive 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 recurrent 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 recurrence are being investigated. Alternative regimens include combination antiviral agents (e.g., lamivudine and adefovir) without routine use of HBIG (Nath et al, 2006). HBV recurrence portends a poor outcome, with a 5-year survival rate of 47% (Saab et al, 2009). For patients with HCC at transplantation, recurrent HBV infection is also significantly associated with a recurrence of HCC after transplantation (Saab et al, 2009).

Hepatitis C Virus

Since its definitive identification in 1989, HCV has been determined 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 individuals 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 compared 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 recipients with extended-criteria livers are significantly worse, and donor age has been reported to affect graft survival adversely (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 malignancy is contraindicated. Conversely, the finding of incidental HCC in the explanted specimen after transplantation for a nonmalignant 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 actuarial 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 transplantation 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 transplantation for patients with solitary tumors smaller than 6.5 cm diameter, 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 treatment 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 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 criteria 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 demonstrate a long-term oncologic benefit to pretransplantation TACE, retrospective data strongly suggest that this may be beneficial, 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 cholangiocarcinoma. 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 transplantation (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 neoadjuvant 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). Retrospective 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 institutions, 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 commonly, 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 available 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).

Nonalcoholic Steatohepatitis (See Chapter 65)

Cirrhosis secondary to nonalcoholic steatohepatitis (NASH) is a rapidly increasing indication for liver transplantation, accounting 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 steatosis, post-OLT obesity, hypertension, DM, hyperlipidemia, use of tacrolimus, and alcoholic cirrhosis as the primary indication for liver transplantation (Dumortier et al, 2010).