266 LIVER TRANSPLANTATION

27.Evan AP, et al. In vivo detection of cavitation in parenchyma of the pig kidney during shock wave lithotripsy. American Urological Association Annual Meeting. Orlando (FL): 2002. p 1500.

28.Willis LR, et al. Effects of SWL on glomerular filtration rate and renal plasma flow in uninephrectomized minipigs. J Endourol 1997;11:27–32.

29.Zhou Y, Cocks FH, Preminger GM, Zhong P. Innovations in shock wave lithotripsy technology: updates in experimental studies. J Urol 2004;172:1892–1898.

30.ZhuS,etal.Reductionoftissueinjuryinshock-wavelithotripsyby using an acoustic diode. Ultrasound Med Biol 2004; 30:675–682.

31.Sheir KZ, et al. Evaluation of synchronous twin pulse technique for shock wave lithotripsy: determination of optimal parameters for in vitro stone fragmentation. J Urol 2003; 170:2190–2194.

32.Paterson RF, et al. Stone fragmentation during shock wave lithotripsy is improved by slowing the shock wave rate: studies with a new animal model. J Urol 2002;168:2211–2215.

33.McAteer JA, et al. Voltage-Stepping During SWL Influences Stone Breakage Independent of Total Energy Delivered: In vitro studies with model stones. American Urological Association Annual Meeting. Chicago: 2003. p 1825.

34.Maloney M, et al. Treatment strategy improves the in vivo stone comminution efficiency and reduces renal tissue injury during shock wave lithotripsy. American Urological Association Annual Meeting. San Antonio (TX): 2005. p 1108.

35.Willis LR, et al. Same-pole application of lowand high-energy shock waves protects kidney from swl-induced tissue injury. American Urological Association Annual Meeting. San Francisco: 2004. p 1114.

36.Sapozhnikov OA, et al. Effect of overpressure and pulse repetition frequency on cavitation in shock wave lithotripsy. J Acoust Soc Am 2002;112:1183–1195.

37.Sokolov DL, et al. Prefocal alignment improves stone comminution in shockwave lithotripsy. J Endourol 2002;16:709–715.

38.Preminger GM. Review: in vivo effects of extracorporeal shock wave lithotripsy: animal studies. J Endourol 1993;7: 375–378.

39.Jan CR, Chen WC, Wu SN, Tseng CJ. Nifedipine, verapamil and diltiazem block shock-wave-induced rises in cytosolic calcium in MDCK cells. Chin J Physiol 1998;41:181–188.

40.Delvecchio F, et al. Citrate and Vitamin E Blunt the SWL Induced Free radical surge in an in-vitro MDCK cell culture model. American Urological Association Annual Meeting. San Francisco: 2004. p 1120.

41.Strohmaier WL, Lahme S, Bichler KH. Amelioration of high energy shock wave induced renal tubular injury by seleniuman in vivo study in rats. American Urological Association Annual Meeting. Anaheim (CA): 2004. p 1529.

42.Yaman O, et al. Protective effect of verapamil on renal tissue during shockwave application in rabbit model. J Endourol 1996;10:329–333.

43.Willis LR, et al. Effects of extracorporeal shock wave lithotripsy to one kidney on bilateral glomerular filtration rate and PAH clearance in minipigs. J Urol 1996;156:1502–1506.

44.Sheng BW, et al. Astragalus membranaceus reduces free radical-mediated injury to renal tubules in rabbits receiving high-energy shock waves. Chin Med J (Engl) 2005;118:43–49.

45.Kehinde EO, et al. The effects of antioxidants on renal damage occuring during treatment of renal calculi by lithotripsy. American Urological Association Annual Meeting. San Antonio (TX): 2005. p 1698.

46.Strohmaier WL, et al. Protective effect of verapamil on shock wave induced renal tubular dysfunction. J Urol 1993;150:27–29.

47.Strohmaier WL, et al. Limitation of shock-wave-induced renal tubular dysfunction by nifedipine. Eur Urol 1994;25:99–104.

48.Ogiste JS, et al. The role of mannitol in alleviating renal injury during extracorporeal shock wave lithotripsy. J Urol 2003;169: 875–877.

49.Heimbach D, et al. The use of chemical treatments for improved comminution of artificial stones. J Urol 2004;171: 1797–1801.

50.Micali S, et al. Efficacy of expulsive medical therapy using nifedipine or tamsulosin after shock wave lithotripsy of ureteral stones. American Urological Association Annual Meeting. San Antonio (TX): 2005. p 1680.

51.Antonio C, et al. May Phyllanthus niruri (Uriston) affect the efficacy of ESWL on renal stnoes? A prospective, randomised short term study. American Urological Association Annual Meeting. San Antonio (TX): 2005. p 1696.

52.Zarse CA, et al. Nondestructive analysis of urinary calculi using micro computed tomography. BMC Urol 2004;4:15.

53.Saw KC, et al. Calcium stone fragility is predicted by helical CT attenuation values. J Endourol 2000;14:471–474.

54.Williams JC, et al. Progress in the use of helical CT for imaging urinary calculi. J Endourol 2004;18:937–941.

See also MINIMALLY INVASIVE SURGERY; ULTRASONIC IMAGING.

LIVER TRANSPLANTATION

PAUL J. GAGLIO

Columbia University College

of Physicians and Surgeons

New York, New York

INTRODUCTION

From a conceptual perspective, liver transplantation involves the replacement of a diseased or injured liver with a new organ. Historically, liver transplantation has emerged from an experimental procedure deemed ‘‘heroic’’ therapy for patients not expected to survive, to the treatment of choice with anticipated excellent long-term outcomes for patients with end stage liver disease. This article will outline the history of and indications for liver transplantation, delineate shortand long-term complications associated with the procedure, and discuss the role of immunosuppressive therapy, intrinsic to the long-term success of the procedure.

HISTORY

Historically, the most significant and persistent impediment to liver transplantation has been the availability of suitable organs. Up until the early 1960s, ‘‘death’’ was defined as cessation of circulation, and thus, donation from deceased donors was thought to be both impractical and impossible, as organs harvested from pulseless, nonperfusing donors would not function when transplanted, due to massive cellular injury. The concept of ‘‘brain death’’ and ability to harvest organs from individuals defined as such first occurred at Massachusetts General Hospital in the early 1960s, when a liver was harvested from a patient whose heart was beating despite central nervous system failure. This seminal event led to the development of a new concept; death was defined when cessation of brain function occurred, rather than the cessation of circulation. Thus, brain dead donors with stable blood pressure and the absence of comorbid disease could serve as potential organ donors. Improvements in the ability to preserve and transport organs dramatically increased organ availability, necessitating a

centralized system to facilitate procurement and allocation of organs to individuals waiting for transplantation. This was initially provided by SEOPF (the Southeast Organ Procurement Foundation), founded in 1968, from which UNOS (the United Network for Organ Sharing) arose. At present, UNOS operates the OPTN (Organ Procurement and Transplantation Network), providing a centralized agency that facilitates recovery and transportation of organs for transplantation, and appropriately matches donors and recipient.

LIVER TRANSPLANTATION: INITIAL RESULTS

The first reported liver transplantation occurred in 1955, in the laboratory of Dr. Stuart Welch (1). In a dog model, an ‘‘auxiliary’’ liver was transplanted into the abdominal cavity, leaving the native liver in situ. Between 1956 and 1960, various investigators initiated experiments in different animal models whereby ‘‘orthotopic’’ liver transplantation was performed, achieved by removal of the native liver and implantation of a ‘‘new’’ liver in its place, requiring anastamoses of the donor and recipient hepatic vein and artery, bile duct, and portal vein (see Fig. 1). These initial attempts at liver transplantation refined the surgical procedure, however, graft dysfunction and death of the animals occurred quickly, due to ineffective immunosuppression and eventual rejection of the liver mediated by the animal’s immune system (2).

The first human liver transplants were performed by Dr. Thomas Starzl in 1963, at the University of Colorado

(3). These early attempts at transplantation highlighted the difficulties associated with extensive abdominal surgery in desperately ill patients, and were associated with poor outcomes, largely due to technical difficulties and the inability to effectively prevent rejection. Similar negative experiences at other centers led to a worldwide moratorium on liver transplantation. However, a major breakthrough in the ability to prevent rejection and prolong the survival of the transplanted liver occurred following the availability of Cyclosporine in 1972 (described below). With continued refinement of the surgical techniques required to perform liver transplantation, combined with the ability to minimize

Suprahepatic vena cava

Infrahepatic vena cava

Portal vein

Bile duct

Hepatic artery

Figure 1. Schematic representation of an orthotopic liver transplant.

organ rejection, posttransplant outcomes improved significantly. From 1963 to 1979, 170 patients underwent liver transplantation at the University of Colorado; 56 survived for 1 year, 25 for 13–22 years, and several remain alive today 30 years after their surgery. Continued improvement in posttransplantation outcomes were achieved, and thus, in 1983, the National Institutes of Health (NIH) established that liver transplantation was no longer considered an ‘‘experimental’’ procedure, rather, as definitive therapy for appropriately selected patients with end-stage liver disease. Additional advances in immunosuppression (reviewed below) including the discovery of polyclonal and monoclonal antibodies to T-cells or their receptors, and other agents such as Tacrolimus, Mycophenolate Mofetil, and Sirolimus have further improved outcomes.

INDICATIONS FOR LIVER TRANSPLANTATION

Liver transplantation is an accepted therapeutic modality for complications of chronic liver disease, or acute liver failure. In general, liver transplantation is recommended when a patient with end stage liver disease manifests signs and symptoms of hepatic decompensation, not controlled by alternative therapeutic measures. This is evidenced by

1.Esophageal and/or gastric variceal bleeding, or bleeding from portal hypertensive gastropathy.

2.Hepatic encephalopathy.

3.Spontaneous bacterial peritonitis.

4.Significant ascites.

5.Coagulopathy.

Patients with liver disease complicated by early stage hepatocellular carcinoma (HCC), often defined as either a single lesion <5 cm or not more than three lesions, each <3 cm are also considered candidates for liver transplantation irrespective of evidence of concomitant hepatic decompen-

sation (4).

If a patient meets these initial criteria, further requirements must be realized. It is generally accepted that liver transplantation is indicated if the patient is not moribund and the transplant is likely to prolong life with a >50% chance of 5-year survival. Furthermore, it is anticipated that the transplant will restore the patient to a range of physical and social function suitable for the activities of daily living. Patients who are suitable candidates should not have comorbid disease with involvement of another major organ system, which would preclude surgery or indicate a poor potential for rehabilitation.

Transplant candidates undergo a thorough psychological assessment prior to liver transplantation. Adequate family and social support must be demonstrated to ensure adherence to the difficult long-term medical regimen that will be required posttransplant. In addition, if a history of substance abuse is present, most transplantation programs require that the patient complete at least 6 months of documented rehabilitation with displayed freedom from alcohol and/or drug recidivism. ‘‘Psycho-social’’ assessment is usually performed by several individuals, including a Psychiatrist or Psychologist and an experienced social worker. In addition, living

268 LIVER TRANSPLANTATION

Table 1. Diseases Associated with Fulminant Hepatic Failure

donor liver transplantation (LDLT), discussed in greater detail below, requires a detailed psychosocial assessment of both recipient and potential donor. In most transplantation centers, an independent donor advocate team consisting of a social worker, internist, and surgeon who are independent of the team evaluating the recipient performs the difficult task of educating a potential donor regarding the risks and benefits of LDLT, assessing motivation to be a donor, and determining if coercion is present.

Another indication for liver transplantation is fulminant hepatic failure, defined as hepatic encephalopathy (confusion) arising in the setting of massive liver injury in a patient without preexisting liver disease. This condition is rapidly fatal unless recovery of hepatic function occurs spontaneously, and thus, emergent liver transplantation may be required. Conditions associated with fulminant hepatic are listed in Table 1.

ETIOLOGY OF LIVER DISEASES REQUIRING LIVER TRANSPLANTATION

Diseases associated with hepatic dysfunction in adults and children are outlined in Tables 2 and 3, respectively. In general, any disease process in adults or children that induces either acute or chronic hepatocellular, biliary, or vascular injury may necessitate liver transplantation. The indications for liver transplantation in children are identical to those in adults, that is, liver transplantation is indicated in the presence of progressive liver disease in patients who fail medical management.

Table 2. Indications for Liver Transplantation

Diseases Effecting Hepatic Parenchyma

Viral hepatitis with cirrhosis (Hepatitis B with or without Delta Virus, Hepatitis C, Non A-E hepatitis)

Autoimmune hepatitis Alcoholic cirrhosis

Metabolic disorders (Wilson’s disease, hemochromatosis, alpha 1 Antitrypsin, Tyrosinemia, protoporphyria, Cystic fibrosis, familial amyloidosis, Neiman-Pick disease)

Fulminant hepatic failure due to any cause Drug induced liver disease

Diseases Effecting Biliary System Primary and secondary biliary cirrhosis Sclerosing cholangitis

Caroli’s disease

Relapsing cholangiohepatitis

Choledochal cysts with obstruction and bilary cirrhosis Hepatic Neoplasia/Malignancies

Patients with nonmetastatic primary hepatocellular carcinoma, with;

A single tumor not > 5 cm

No more than three lesions with the largest lesion < 3 cm No thrombosis of the portal or hepatic vein

Hemangioendothelioma (confined to the liver) Neuro endocrine tumors with hepatic involvement Large hepatic Hemangioma

Miscellaneous Causes

Hepatic vein thrombosis (Budd-Chiari syndrome) Portal vein thrombosis

Hepatic artery thrombosis Trauma

Many of the disease processes in adults that induce liver failure are recapitulated in children. However, specific disease states seen in children including metabolic diseases and congenital biliary anomalies represent additional indications for liver transplant. Moreover, liver transplantation is indicated in infants and children if the transplant will prevent or attenuate derangements in cognition, growth, and nutrition. Therefore, children should be considered for liver transplantation when there is evidence that hepatic decompensation is either unavoidable(basedonknowledgeofthehistoryofthediseaseitself), imminent, or has already occurred. The clinical scenarios that determine when liver transplantation is required in children can include one or more of the following:

1.Intractable cholestasis.

2.Portal hypertension with or without variceal bleeding.

3.Multiple episodes of ascending cholangitis.

4.Failure of synthetic function (coagulopathy, low serum albumin, low cholesterol).

5.Failure to thrive or achieve normal growth, and/or the presence of cognitive impairment due to metabolic derangements, and malnutrition.

6.Intractable ascites.

7.Encephalopathy.

8.Unacceptable quality of life including failure to be able to attend school, intractable pruritis.

9.Metabolic defects for which liver transplantation will reverse life-threatening illness and/or prevent irreversible central nervous system damage.

10.Life threatening complications of stable liver disease (e.g., hepatopulmonary syndrome).

CONTRAINDICATIONS TO LIVER TRANSPLANTATION (ADULTS AND CHILDREN)

At present, ‘‘absolute exclusion’’ criteria for liver transplantation are evolving. In general, patients with advanced cardiac or pulmonary disease, severe pulmonary hypertension, active substance abuse, coma with evidence of irreversible central nervous system injury, sepsis, or uncorrectable congenital abnormalities that are severe and life threatening are not transplant candidates. In addition, individuals with evidence of extrahepatic malignancy do not meet criteria for transplantation, unless the patient meets standard oncologic criteria for ‘‘cure’’. ‘‘Relative’’ exclusion criteria include renal insufficiency when renal transplantation is not feasible, prolonged respiratory failure requiring >50% oxygen, advanced malnutrition, primary biliary malignancy, inability to understand the risk/benefits of the procedure, and inability to comply with medications and conform to follow-up regimens. Recent data indicates successful outcomes in HIV infected patients who undergo liver transplantation, a population formerly considered noncandidates for the procedure. However, initial enthusiasm regarding successful transplantation out-

comes must be restrained by evidence that HCV recurrence in HIV–HCV coinfected patients may be problematic (5).

RECIPIENT CHARACTERISTICS AND PRIORITIZATION FOR TRANSPLANTATION

Given the relatively stable number of available donor organs in the setting of a rapidly expanding pool of potential recipients, the timing of transplantation is critical. Liver transplantation in a stable patient who is anticipated to do well for many years while waiting for an available organ may not be appropriate, while liver transplantation in a moribund patient with a low probability of posttransplantation survival is similarly inappropriate. Prior to 1997, prioritization for liver transplantation was based on the location where patients received their care (i.e., home, hospital, intensive care unit) and waiting time on the transplant list. In 2002, several policies were instituted by UNOS in an attempt to produce a more equitable organ allocation scheme. Waiting time and whether the patient was hospitalized were eliminated as determinants of prioritization of organ allocation. The ‘‘MELD’’ score (Model for End Stage Liver Disease) a logarithmic numerical score based on the candidate’s renal function (creatinine), total bilirubin, and INR (international normalized ratio for prothrombin time) has been shown to be the best predictor of

270 LIVER TRANSPLANTATION

mortality among cirrhotic patients, including those on the transplant waiting list. It was therefore adopted by UNOS as a mechanism to prioritize waiting list candidates. MELD had been validated as a predictor of 3-month survival in diverse groups of patients with various etiologies and manifestations of liver disease (6). Presently, a patient’s position on the liver transplantation waiting list is now determined by their MELD score; patients with highest MELD scores are ranked highest on the list. Prospective analysis of the impact of MELD indicates improvement in both the rate of transplantation, pretransplantation mortality, and short-term posttransplantation mortality rates (7). However, retrospective analysis has suggested that posttransplantation survival may be reduced in patients with very high pretransplantation MELD score, particularly in Hepatitis C infected patients

(8). Conversely, MELD score effectively delineates when a patient is ‘‘too well’’ for transplantation. A recent review indicates that posttransplantation survival in patients transplanted with a MELD score of <15 is lower than a nontransplanted cohort with similar MELD score (9). Thus, it is clear that careful recipient selection, with attention to pressor and ventilatory requirements, need for dialysis, age, and MELD score are important factors in selecting appropriate candidates for liver transplantation.

LIVER TRANSPLANTATION: SOURCE OF ORGANS

At present, there are three potential types of organ donors specific to liver transplantation, identified as deceased, living, or non-heart beating. Deceased donors (DD) comprise the majority of liver donors. Either by self-identification while living, or after discussion with ‘‘next of kin’’ when donor brain death has been declared, individuals are acknowledged as potential organ donors. Recent data from UNOS indicate that 1- and 3-year patient survival in recipients of DD liver transplant is 81 and 71%, respectively (10). However, despite efforts to maximize utilization of organs acquired from DD including the use of older donors, steatotic (fatty) livers, and livers infected with Hepatitis C or B, a growing disparity exists between the number of available livers and the number of individuals waiting for transplantation. This critical shortage of organs has resulted in both an increase in the waiting time for liver transplantation and death rate among patients on the waiting list. In response, the modalities of adult-to-child and adult-to-adult LDLT have emerged as alternatives to deceased donor liver transplantation (11,12). Adult-to-child LDLT usually involves the removal of the left lateral segment of the liver ( 20% of hepatic mass) from an adult donor for implantation into a child, while adult to adult living donor liver transplantation requires that the larger, right lobe of the liver (which accounts for 50–60% of the hepatic mass) be removed from the donor to ensure adequate hepatic mass in the recipient. Rapid regeneration of the liver remnant in the donor and the partial allograft transplanted into the recipient occurs, to the extent that appropriate liver volume is restored within 1–2 months in both donor and recipient following surgery. Since most pediatric LDLT recipients are <2-years old, they receive a liver graft of

adequate or even excessive size, and thus liver insufficiency due to the receipt of inadequate liver mass is rare. In contradistinction, as the recipient of an adult-to-adult living donor liver transplantation receives a graft that must over time grow to an appropriate volume, selection of recipients best able to tolerate transplantation of a ‘‘partial’’ graft is necessary. In appropriately selected pediatric and adult recipients, 1- and 3-year graft and patient survival in individuals who undergo LDLT is similar or superior to DD (10). However, when comparing postoperative complications in recipients of DD versus LDLT, recipients of LDLT have a greater rate of biliary complications including bile leaks and biliary strictures, which occur in 15–32% of patients (13). In addition, the ‘‘small-for-size syndrome’’ manifested as prolonged posttransplantation cholestasis with or without portal hypertension may occur following LDLT, if the graft is of inadequate size (14). Fortunately, the majority of patients who experience this syndrome recover without the requirement of retransplantation.

Recently, significant interest in the utilization of ‘‘nonheart beating’’ donors (donation after cardiac death, DACD) as a potential modality to further increase the pool of available organs has emerged. In contrast to DD who are declared brain dead, DACD are critically ill patients who are not brain dead, but have no expectation of recovery and who based on their own prior wishes or families request are removed from life support. Following cardiac arrest and declaration of death, organs are harvested. There are two types of DACD, ‘‘controlled’’ and ‘‘uncontrolled’’. In the controlled DACD (Maastricht category 3 ‘‘death anticipated’’) the patient is removed from life support and death occurs in the operating room. Once death has been declared, organs deemed suitable for transplantation are rapidly perfused with preservation solution and removed surgically. The uncontrolled DACD (Maastricht category 1 and 2 ‘‘death not anticipated’’) is declared dead after cardiac arrest, rushed to the operating room, and organs are harvested. Uncontrolled DACD are usually not utilized for liver transplantation due to the high rate of primary nonfunction (defined below), usually due to prolonged ischemia of the graft. When utilizing controlled DACD for transplantation, emerging data indicates that recipient and graft survival are diminished when compared to deceased and living donor liver transplantation with a higher incidence of primary nonfunction, biliary injury, and requirement for retransplantation. However, several centers have reported acceptable outcomes when utilizing controlled DACD organs, particularly those without significant ischemia in well-selected recipients (15).

Finally, ‘‘domino’’ transplantation is an option for patients afflicted with familial amyloidotic polyneuropathy (FAP). Familial amyloidotic polyneuropathy is a fatal disease caused by an abnormal amyloidogenic transthyretin (TTR) variant generated by the liver. Liver transplantation in these patients removes the source of the variant TTR molecule, and represents the only known curative treatment. As no intrinsic liver disease exists in patients affected by FAP, the liver explanted from a patient with FAP may be transplanted into another patient, thus, allowing ‘‘domino’’ transplantation. Survival in both recipients of FAP livers and transplanted FAP patients has

been reported to be excellent and comparable to survival with OLT performed for other chronic liver disorders (16).

POSTTRANSPLANTATION MANAGEMENT

The complex nature of the surgical procedure utilized to both explant (remove) the diseased, cirrhotic liver and implant (transplant) the new allograft into the recipient make it intuitive that the majority of the early complications following liver transplantation are technical and related to the surgical procedure itself. However, following the first postoperative days, and as patients progress to the first month posttransplantation and beyond, the nature and variety of complications change. Early complications (within the first 2 months) and late complications (beyond 2 months) may negatively affect patient and graft survival (Table 4). Complications specific to the surgical procedure and those that directly affect the transplanted organ are discussed below.

EARLY COMPLICATIONS

Primary Nonfunction and Early Graft Dysfunction

A major threat to the newly transplanted liver is primary graft nonfunction (PNF). This syndrome defined as acidosis, rising INR, progressive elevation in liver transaminases and creatinine, and decreases in mentation occurs when the newly transplanted liver allograft fails to function normally. The mechanisms responsible for this phenomenon are complex, and relate to donor factors,

Table 4. Early and Late Complications Following Liver

Transplantation

Early

Graft Specific Primary nonfunction

Early graft dysfunction Hepatic artery thrombosis

Hepatic and portal vein thrombosis

Preservation injuryBiliary complications: bile leak, biliary stenosis

Acute cellular rejection Other

Bacterial and fungal infection CMV infection

Recurrent Hepatitis B and C

Late

Graft Specific Chronic rejection

Recurrence of primary disease Other

Hypertension

Hyperlipidemia Diabetes Obesity Cardiac disease

Renal dysfunction

Fungal infection (Cryptococcus, Aspergillus) CMV

Posttransplant lymphoproliferative disorder Nonhepatic malignancy: i.e., skin cancer

inadequate preservation of the liver, prolonged ischemia, extensive steatosis of the graft, hepatic artery thrombosis (see below) or immune response to the implanted organ (17). In the setting of PNF, a rapid assessment of hepatic artery flow needs to occur, as immediate surgical repair of a thrombosed hepatic artery may reverse PNF. In the absence of hepatic artery thrombosis, emergent retransplantation is required for PNF.

In contrast to PNF, early graft dysfunction (EGD) is manifested by an early rise in serum transaminases to values > 2000–3000 IU/L, cholestasis with rising Bilirubin levels, without marked coagulopathy or impairment in mental status and renal function. EGD may occur in the setting of ischemic injury or steatosis in the graft, and typically occurs within the first 24–48 h after the transplant. Unlike PNF, the manifestations of EGD usually improve with supportive care, and emergency retransplantation is not necessary.

Hepatic Artery Thrombosis

A potentially devastating posttransplantation complication is hepatic artery thrombosis (HAT). Hepatic artery thrombosis occurs more commonly in pediatric transplant recipients compared to adults due to the technical difficulties associated with the anastomosis of smaller size vessels. In HAT, the immediate postoperative period may be associated with graft failure, elevation in serum liver transaminases, bile leak, hepatic necrosis, and sepsis. Since the blood supply to the biliary tree in the early posttransplant period is principally from the hepatic artery, HAT is frequently associated with irreversible injury to the biliary tract (18). Thus, HAT in the first 7 days after liver transplantation is an indication for emergent artery repair or retransplantation.

Due to the potentially devastating consequences of HAT, most transplant centers screen for this complication with duplex-ultrasound (US) in the immediate posttransplant period. If duplex-US suggests HAT, angiography is usually performed to confirm the diagnosis, and if present, surgical revision of the hepatic artery is required. If surgical repair cannot be achieved, liver retransplantation may be necessary.

PORTAL AND HEPATIC VEIN THROMBOSIS

Though less common than HAT, thrombosis of the portal and/or hepatic veins in the immediate posttransplant period can also adversely affect patient and graft survival. Acute ‘‘Budd-Chiari’’ syndrome due to hepatic vein or vena cava thrombosis is associated with abdominal pain, peripheral edema, and the threat of graft failure, as hepatic congestion in the newly transplanted liver is poorly tolerated. In this circumstance, emergency thrombectomy and surgical revision is required. Acute portal vein occlusion may be associated with exacerbation of preexisting portal hypertension, associated with gastrointestinal bleeding from porto-systemic collateral vessels such as esophageal and gastric varices. Acute portal vein thrombosis is managed by surgical repair, while chronic portal vein thrombosis may be well tolerated. A potential alternative to surgical repair for both hepatic and portal vein stenosis or occlusion is thrombolysis and/or the placement of

272 LIVER TRANSPLANTATION

endovascular stents by an experienced interventional radiologist (19).

ACUTE CELLULAR REJECTION

Rejection of any transplanted organ is a constant threat, as immunologic recognition of the graft as ‘‘foreign’’ may be associated with injury. However, compared to other organs, liver allografts are relatively privileged immunologically, and thus, the incidence and consequences of acute cellular rejection (ACR) are diminished when compared to other solid organs utilized for transplantation. The reported incidence of ACR within the first posttransplant year is 30–50%, in most cases, usually occurring within the first 2–3 weeks postoperatively. The clinical presentation is variable; ACR may be asymptomatic, or associated with fever or abdominal pain. Laboratory findings include elevation or failure of normalization of serum transaminases, usually in association with a rising alkaline phosphatase and/or bilirubin. The diagnosis of acute liver graft rejection is confirmed by liver biopsy and examination of liver histology (20). Conventional histologic criteria associated with ACR include the presence of periportal lymphocytic infiltrate, as well as bile duct and hepatic vascular endothelial cell injury. Most cases of ACR respond to treatment with intravenous bolus glucocorticoids. Approximately 10% of patients with ACR will not improve with intravenous glucocorticoids, requiring the administration of monoclonal or polyclonal anti-T cell antibodies (reviewed below). Mild and moderate ACR may also respond to either increasing the dose of the primary immunosuppressive agent, or switching to an alternate calcineurin inhibitor. This approach has been used with increasing frequency, particularly in patients transplanted for HCV and HBV due to concerns regarding the negative impact of over-immunosuppression on viral recurrence.

BILIARY COMPLICATIONS

Bile leaks and strictures generally occur at the anastomosis of the donor and recipient bile ducts, recognized by a rise in serum bilirubin and/or alkaline phosphatase or by the presence of bile in surgical drains in the immediate posttransplantation period. The incidence of biliary complications is between 5 and 15% following deceased donor liver transplantation. However, between 15 and 30% of patients who undergo living donor liver transplantation develop biliary complications, due to the complexity of the biliary reconstruction required (21). In both deceased and living donor recipients, the majority of bile leaks resolve spontaneously without the need for reoperation. As previously stated, the biliary tree receives the vast majority of its blood supply from the hepatic artery, and thus, the adequacy of hepatic artery blood flow needs to be evaluated in the setting of any biliary injury. If spontaneous resolution of the bile leak does not occur, endoscopic or radiologic placement of a biliary stent across the biliary anastamoses is often successful (22). In some cases, surgical exploration and revision of the biliary anastamoses with a Roux-en-Y choledochojejunostomy may be required.

Anastamotic biliary strictures require careful attention, as if left untreated, cholangitis, graft dysfunction, and eventually secondary biliary cirrhosis may occur. Techniques for management include dilatation and stenting via biliary endoscopy or percutaneous transhepatic cholangiogram by an interventional radiologist. If these modalities are unsuccessful, surgical revision of the biliary anastamosis with a Roux-en-Y choledochojejunostomy may be required. In rare cases with diffuse stricturing, retransplantation may be necessary.

ISCHEMIC AND PRESERVATION INJURY

The newly transplanted liver is always subjected to some degree of ischemic injury (23). Cold (or hypothermic) ischemia is unavoidable, as it occurs prior to transplantation while the liver is cooled in preservation solution, awaiting implantation. Warm (normothermic) ischemia occurs during the transplantation procedure itself, when hepatic blood flow is interrupted to minimize blood loss during transplantation, or when the formerly ‘‘cooled’’ liver is subjected to body temperature during transplantation. Cold ischemia is usually well tolerated, while in contrast, warm ischemia often leads to death of hepatocytes, with resultant elevation in serum transaminases, apoptosis and centrilobular necrosis. In the setting of significant warm ischemia, graft failure may result. Several investigators have noted improvement in ischemic injury and enhanced graft and patient outcomes by employing a technique described as ‘‘ischemic preconditioning’’ defined as a brief period of controlled ischemia followed by a short interval of reperfusion before the actual surgical procedure (24). This is accomplished during liver transplantation by transiently interrupting hepatic inflow by placing a vascular clamp or a loop around the portal triad (i.e., portal vein, hepatic artery, and bile duct), rendering the whole organ ischemic for 10–15 min, after which the clamp is removed and the liver is reperfused. This technique may be of particular benefit in organs with significant steatosis.

Complications Beyond Two Months

Progress in the surgical techniques required to perform transplantation, the treatment of postoperative complications and prevention of rejection have been associated with significant improvements in short-term morbidity and mortality following transplantation. Coincident with improvements in short-term outcomes has been a rise in long-term complications. These complications, including side effects of chronic immunosuppression, neoplasia, and infections are discussed in detail elsewhere. Long-term complications that affect the transplanted liver are discussed below.

CHRONIC REJECTION

Chronic allograft rejection or ‘‘vanishing bile duct syndrome’’ is rare, but in contradistinction to acute cellular rejection, a much more difficult to treat complication. Diagnostic criteria for chronic rejection include bile duct atrophy affecting the majority of bile ducts, with or without bile duct loss. Arterial and venous injury affecting the

large branches of the hepatic artery or portal vein (foamy arteriopathy) may also be present (24). Risk factors for chronic liver rejection include transplantation for primary sclerosing cholangitis, primary biliary cirrhosis, HLA mismatch between donor and recipient, and cytomegalovirus infection. Chronic rejection is usually a harbinger of poor outcomes, often resulting in the requirement for retransplantation; altering immunosuppression is rarely associated with improvement.

Recurrence of Primary Disease Following Liver

Transplantation

A major challenge to the liver transplant community is recurrence of the primary disease that caused the patients native liver to fail. Diseases that do not recur following liver transplantation include congenital anatomic anomalies (e.g., biliary atresia, polycystic liver disease, Caroli’s disease, Alagilles syndrome, congenital hepatic fibrosis) and metabolic diseases of the liver (e.g., Wilson’s disease, alpha 1 antitrypsin deficiency). However, all other causes of liver disease including primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis, nonalcoholic fatty liver disease, hemochromatosis and alcohol related liver disease have been reported to recur after liver transplantation. In some cases, recurrent disease may lead to significant liver injury with resultant graft failure (26–30). Disease processes most commonly associated with recurrence include viral hepatitis B (HBV) and C (HCV). The recurrence of HBV is associated with uniformly poor outcomes with graft failure and death. Fortunately, recurrence of HBV after liver transplantation can be prevented by administering hepatitis B immune globulin (HBIG) at the time of transplantation and at regular intervals thereafter, with or without the use of antiviral agents such as Lamivudine and Adefovir. In contradisctinction to HBV, HCV recurrence following liver transplantation remains a significant source of morbidity and mortality, with negative impact on post-transplantation outcomes. In patients with active HCV replication prior to transplantation, reacquisition of viremia following transplantation is universal, and histologic injury due to HCV occurs in up to 90% of patients followed for 5 years (31). Although histologic injury in the allograft due to HCV is exceedingly common, disease progression after the development of hepatitis is variable, with some patients experiencing indolent disease and others rapidly progressing to cirrhosis and liver failure. In patients that develop HCV associated cirrhosis posttransplantation, up to 42% will experience decompensation manifested as ascites, encephalopathy, or hepatic hydrothorax, and <50% of patients survive >1 year after the development of decompensation (32). It is important to contrast the natural history of HCV before and after transplant; prospective and retrospective data are emerging which indicate that the progression of HCV following liver transplantation is accelerated when compared to the nonimmunosuppressed pretransplant patient population.

Whether HCV recurrence is more severe in recipients of LDLT than in DD recipients is controversial. Although several recent reports indicate that HCV recurrence may be more problematic in recipients of LDLT when compared to DD (33), particularly the cholestatic variant of HCV (34),

other authors have noted no differences in outcomes in HCV infected patients who undergo LDLT when compared to DD (35,36). At present, both the optimal timing for transplant in HCV patients and the therapy for recurrent HCV following liver transplantation are incompletely described. Theoretically, eradication of HCV prior to liver transplantation in patients with decompensated liver disease would be beneficial, although in practice, this strategy has been marred by exacerbation of encephalopathy, infections, and other serious adverse events, particularly in patients treated with high dose Interferon and ribavirin (37). A novel approach including initiating therapy with low dose interferon (including Pegylated interferon preparations) and ribavirin with slow escalation in dose may be associated with improved tolerability and efficacy (38). Following liver transplantation, both preemptive therapy prior to the development of histologic injury and directed therapy after the onset of liver injury have been attempted with varying degrees of success. It is important to note, however, that posttransplantation, tolerability of interferon preparations, and ribavirin is suboptimal. Significant leucopenia and anemia are common, likely due to drug induced bone marrow suppression and renal insufficiency potentiating ribavirin induced hemolysis (39).

Immunosuppressive Medications

A cornerstone to posttransplantation management is the ability to prevent or attenuate immunologic rejection of the transplanted graft, which when left untreated, can be associated with graft failure. From a conceptual standpoint, understanding how recognition of the newly engrafted liver as ‘‘foreign’’ occurs, how to modulate immune mediated injury, and at the same time prevent ‘‘overimmunosuppression’’ are critical to achieve optimal post transplantation outcomes. The various immunosuppressive medications and their mechanism of action currently utilized in liver transplant recipients are listed in Table 5. Unfortunately, all immunosuppressive therapy is associated with undesired effects, with the potential for additive effects when agents are combined. In general, most transplant centers utilize three agents to prevent allograft rejection in the immediate posttransplant period, utilizing a combination of a calcineurin inhibitor such as Cyclosporine (CYA) or Tacrolimus (TAC), a second agent such as Mycophenolate mofetil (MMF) or Azathioprine (AZA), and a glucocorticoid such as Prednisone. As patients achieve adequate liver function and freedom from rejection beyond 6-months posttransplantation, satisfactory immunosuppression can be achieved in many patients with monotherapy, usually with a calcineurin inhibitor, although in patients who are at increased risk of rejection such as those with autoimmune hepatitis, primary biliary cirrhosis, or sclerosing cholangitis, long-term immunosuppression is achieved with a combination of a calcineurin inhibitor with either low dose MMF or Prednisone (40).

Corticosteroids

Corticosteroids achieve their desired immunosuppressive affects by the suppression of leukocyte, macrophage, and cytotoxic T-cell activity, and diminution of the effect of

cytokines, prostaglandins, and leukotrienes. However, hypertension, dyslipidemia, glucose intolerance, bone loss, peptic ulcers and psychiatric disorders are often associated with therapy. Therefore, a strategy to taper and discontinue glucocorticoids within the first 6 months–1 year following transplantation while maintaining adequate levels of calcineurin inhibitor is employed by many transplant centers. This tactic is often altered in patients who undergo liver transplantation secondary to an immunologic disorder such as autoimmune hepatitis, primary biliary cirrhosis and sclerosing cholangitis due to an enhanced risk of acute cellular rejection. In these patients,eitherlong-termuseofcorticosteroidswithanattempt to minimize doses is advocated, or chronic use of MMF or AZA in combination with a calcineurin inhibitor is required.

T-Cell Depleting Agents

In the past, ‘‘induction therapy’’ with antilymphocyte agents such as antilymphocyte globulin or antithymocyte

globulin or monoclonal antibody preparations such as OKT3 was utilized immediately after liver transplantation to rapidly induce an immune suppressed state via the rapid destruction of the host’s T cells. However, due to significant systemic side effects including fevers, allergic reactions, serum sickness, and thrombocytopenia, the use of these agents is now usually reserved for the treatment of glucocorticoid resistant rejection, or less commonly, in patients with severe renal insufficiency in an attempt to delay the use of either CYA or TAC, which may be associated with worsening of renal function (41).

IL-2 Receptor Blockers

T-cell activation and proliferation following presentation of a foreign antigen requires the induction of several cytokines, including IL-2 (interleukin 2). Antibodies directed against the interleukin (IL)-2 receptor are effective for initial immunosuppression, as IL-2 receptor blockade

down regulates IL-2 mediated T-cell proliferation. The IL-2 receptor antibodies such as Basiliximab and Daclizumab, given intravenously at the time of transplant and during the first posttransplantation week can reduce the incidence of acute liver graft rejection when utilized in combination with a calcineurin inhibitor, although these agents may not be sufficient to prevent rejection when utilized alone. The IL-2 receptor antibodies are generally well tolerated, although side effects may include infections, gastrointestinal distress, and rarely, pulmonary edema and bronchospasm. As these agents rarely induce renal dysfunction, many transplant programs utilize IL-2 receptor antibodies as ‘‘induction’’ therapy in individuals with renal insufficiency at the time of transplantation (42), in an attempt to delay initiation or diminish dose of calcineurin inhibitors, which may exacerbate renal insufficiency.

Calcineurin Inhibitors

IL-2 inhibition effectively suppresses T-Cell activation. Cyclosporine and TAC achieve this by binding to cytoplasmic receptors, forming complexes which inactivate calcineurin, a key enzyme in T-cell signaling. The major side effects of both CYA and TAC include hypertension, renal insufficiency, and neurologic complications. However, there is evidence to suggest that obesity, hyperlipidemia, hirsutism, and gingival hyperplasia occur more commonly in patients who receive CYA, while a higher rate of diarrhea, insulin resistance, and diabetes is seen in patients who receive TAC. In response to inconsistent absorption of standard Cyclosporine, the development of a microemulsified formulation of cyclosporine (e.g., Neoral) has allowed consistent blood levels (43). Given their efficacy and oral administration, calcineurin inhibitors have a central role in posttransplant immunosuppression.

Safety and efficacy of calcineurin inhibitors is generally assessed by monitoring blood levels drawn prior to the dose (trough), although several investigators describe that blood levels drawn 2 h after a dose of Cyclosporine (i.e., C2 levels) rather than trough levels more accurately indicate exposure to drug. At many transplantation centers, the definition of appropriate target level of calcineurin inhibitor is linked to the patients time posttransplantation; in general, higher levels are required in the first several months postoperatively while the threat of rejection is acute. The target levels for calcineurin inhibitors can be appropriate adjusted downward as patients achieve both normal liver function and freedom from rejection months to years following surgery. In addition, a philosophy of minimizing exposure to high levels of calcineurin inhibitors in HBV or HCV infected patients is adopted by many transplant centers, due to the negative impact of ‘‘overimmunosuppression’’ on viral replication and disease recurrence.

Antiproliferative Agents

Antiproliferative agents such as AZA and MMF prevent the expansion of activated T cells and B cells and regulate immune mediated injury. Azathioprine, a purine analogue, is metabolized in the liver to its active compound, 6-mer- captopurine, which inhibits adenosine and guanine production, thus inhibiting DNA and RNA synthesis in rapidly

proliferating T cells. Mycophenolate Mofetil is a potent noncompetitive inhibitor of inosine monophosphate dehydrogenase (IMPDH), an enzyme necessary for the synthesis of guanine, a purine nucleotide. Mycophenolate Mofetil, when used in combination with a calcineurin inhibitor and steroids has been shown to be associated with lower rejection rates in the first 6 months posttransplantation when compared to AZA (44). The major toxicities associated with the use of either MMF or AZA are bone marrow suppression with resultant leukopenia, anemia, and thrombocytopenia, though this is more marked with AZA. Mycophenolate Mofetil has been associated with a greater incidence of dyspepsia, peptic ulcers, and diarrhea when compared to AZA, while pancreatitis may occur in individuals prescribed AZA. These side effects usually abate by dose reduction or discontinuation. The majority of transplant centers utilize a combination of a Calcineurin inhibitor with either MMF or, less commonly, AZA for at least the first 3–6 months posttransplantation. Since AZA and MMF do not cause renal insufficiency, they can be utilized in a strategy to minimize or avoid calcineurin inhibitor use, particularly in patients with renal dysfunction.

Other Immunosuppressive Agents

The limitations and untoward effects of available immunosuppressive agents have induced research and development of alternative agents. Sirolimus (Rapamycin) (RAPA) and its derivative Everolimus represent a new class of compounds, which achieve their immuosuppressive effect by inhibiting mTOR (target of Rapamycin). Inhibition of mTOR diminishes intracellular signaling distal to the IL-2 receptor and prevents T-cell replication. As the lymphoproliferative pathways inhibited by RAPA and Everolimus are distinct from those affected by calcineurin inhibitors, investigators have utilized these agents in combination with calcineurin inhibitors to achieve synergistic effect. However, enthusiasm for RAPA has been tempered by recent data showing higher rates of hepatic arterial thrombosis in patients who receive RAPA in the weeks immediately following transplantation (45). In addition, impaired wound healing has been noted in patients who receive RAPA, potentially due to impairment of granulation mediated by inhibition of TGF-b. Leukopenia, thrombocytopenia, and hyperlipidemia are the principal toxicities associated with RAPA and Everolimus. Recent reports of pneumonitis in RAPA treated patients have also emerged. A positive attribute of both RAPA and Everolimus is the absence of renal toxicity; some data suggest that post transplantation renal insufficiency can be reversed when calcineurin inhibitors are withdrawn and RAPA is initiated (46). Newer immunosuppressive agents will continue to be developed; it is hoped that these agents will be associated with diminished shortand long-term toxicity and facilitate a state of ‘‘immune tolerance’’ of the graft that will ultimately allow minimization of the requirement for immunosuppressive medications.

SUMMARY

Liver transplantation is the treatment of choice for appropriately selected patients with end stage liver disease.

276 LIVER TRANSPLANTATION

Over the last several decades, significant advances in surgical technique and immunosuppression, selection of appropriate donors, grafts, and recipients, and improved therapies to prevent and treat postoperative complications have greatly improved posttransplantation outcomes. Despite these impressive achievements, many challenges remain. It is becoming increasingly apparent that the growing disparity between the number of liver transplant candidates and available organs will be associated with escalating death rates on the transplant waiting list. Enhanced posttransplantation survival has led to the emergence of complications associated with patient longevity, including nonhepatic disease, complications of immunosuppression, infections, neoplasia, and recurrence of the primary disease for which the liver transplantation was indicated. Further progress in liver transplantation will be achieved by maximizing the use of available organs, refinement and exploration of alternatives to deceased donor liver transplantation, improvements in immunosuppression, and enhanced recognition and treatment of longterm complications, particularly recurrent liver disease.

BIBLIOGRAPHY

1.Welch CS. A note on transplantation of the whole liver in dogs. Transplant Bull 1955;2:54.

2.Kukral JC, Littlejohn MH, Williams RK, Pancer RJ, Butz GW Jr, Starzl TE. Hepatic function after canine liver transplantation. Arch Surg 1962;85:157–165.

3.Starzl TE, Marchioro TL, Porter KA, Brettschneider L. Related Articles, Homotransplantation of the liver. Transplantation 1967;5(Suppl):790–803.

4.Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, Montalto F, Ammatuna M, Morabito A, Gennari L. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334: 693–699.

5.Moreno S, Fortun J, Quereda C, Moreno A, Perez-Elias MJ, Martin-Davila P, de Vicente E, Barcena R, Quijano Y, Garcia M, Nuno J. Martinez Liver transplantation in HIV-infected recipients. Liver Transpl 2004;11:76–81.

6.Kamath PS, Wiesner RH, Malinchoc M, Kremers W, Therneau TM, Kosberg CL, D’Amico G, Dickson ER, Kim WR. A model to predict survival in patients with endstage liver disease. Hepatology 2001;33:464–470.

7.Freeman RB, Wiesner RH, Edwards E, Harper A, Merion R, Wolfe R. United Network for Organ Sharing Organ Procurement and Transplantation Network Liver and Transplantation Committee. Results of the first year of the new liver allocation plan. Liver Transpl 2004;10:7–15.

8.Onaca NN, Levy MF, Sanchez EQ, Chinnakotla S, Fasola CG, Thomas MJ, Weinstein JS, Murray NG, Goldstein RM, Klintmalm GB. A correlation between the pretransplantation MELD score and mortality in the first two years after liver transplantation. Liver Transpl 2003;9:117–123.

9.Merion RM, Schaubel DE, Dykstra DM, Freeman RB, Port FK, Wolfe RA. The survival benefit of liver transplantation. Am J Transpl 2005;5:307–313.

10.http://www.UNOS.org.

11.Broelsch CE, Whitington PF, Emond JC, Heffron TG, Thistlethwaite JR, Stevens L, Piper J, Whitington SH, Lichtor JL. Liver transplantation in children from living related donors. Surgical techniques and results. Ann Surg 1991;214: 428–437.

12.Marcos A. Right-lobe living donor liver transplantation. Liver Transpl 2000;6:S59–S63.

13.Shiffman ML, Brown RS Jr., Olthoff KM, Everson G, Miller C, Siegler M, Hoofnagle JH. Living donor liver transplantation: summary of a conference at The National Institutes of Health. Liver Transpl 2002;8:174–188.

14.Emond JC, Renz JF, Ferrell LD, Rosenthal P, Lim RC, Roberts JP, Lake JR, Ascher NL. Functional analysis of grafts from living donors. Implications for the treatment of older recipients. Ann Surg 1996;224:544–552.

15.Otero A, Gomez-Gutierrez M, Suarez F, Arnal F, FernandezGarcia A, Aguirrezabalaga J, Garcia-Buitron J, Alvarez J, Manez R. Liver transplantation from maastricht category 2 non-heart-beating donors: A source to increase the donor pool? Transpl Proc 2004;36:747–750.

16.Ericzon BG, Larsson M, Herlenius G, Wilczek HE. Familial Amyloidotic Polyneuropathy World Transplant Registry. Report from the Familial Amyloidotic Polyneuropathy World Transplant Registry (FAPWTR) and the Domino Liver Transplant Registry (DLTR). Amyloid 2003;10:67–76.

17.Schemmer P, Mehrabi A, Kraus T, Sauer P, Gutt C, Uhl W, Buchler MW. New aspects on reperfusion injury to liver– impact of organ harvest. Nephrol Dial Transpl 2004;19:26–35.

18.Bhattacharjya S, Gunson BK, Mirza DF, Mayer DA, Buckels JA, McMaster P, Neuberger JM. Delayed hepatic artery thrombosis in adult orthotopic liver transplantation-a 12-year experience. Transplantation 2001;71:1592–1596.

19.Vignali C, Cioni R, Petruzzi P, Cicorelli A, Bargellini I, Perri M, Urbani L, Filipponi F, Bartolozzi C. Role of interventional radiology in the management of vascular complications after liver transplantation. Transpl Proc 2004;36:552–554.

20.Lefkowitch JH. Diagnostic issues in liver transplantation pathology. Clin Liver Dis 2002;6:555–570.

21.Fondevila C, Ghobrial RM, Fuster J, Bombuy E, GarciaValdecasas JC, Busuttil RW. Biliary complications after adult living donor liver transplantation. Transpl Proc 2003;35: 1902–1903.

22.Denys A, Chevallier P, Doenz F, Qanadli SD, Sommacale D, Gillet M, Schnyder P, Bessoud B. Interventional radiology in the management of complications after liver transplantation. Eur Radiol 2004;14:431–439.

23.Selzner N, Rudiger H, Graf R, Clavien PA. Protective strategies against ischemic injury of the liver. Gastroenterology 2003;125:917–936.

24.Clavien PA, Yadav S, Sindram D, Bentley RC. Protective effects of ischemic preconditioning for liver resection performed under inflow occlusion in humans. Ann Surg 2000;232: 155–162.

25.Demetris A, Adams D, Bellamy C, Blakolmer K, Clouston A, Dhillon AP, Fung J, Gouw A, Gustafsson B, Haga H, Harison D, Hart J, Hubscher S, Jaffe R, Khettry U, Lassman C, Lewin K, Martinez O, Nakazawa Y, Neil D, Pappo O, Parizhskaya M, Randhawa P, Rasoul-Rockenschaub S, Reinholt F, Reynes M, Robert M, Tsamandas A, Wanless I, Wiesner R, Wernerson A, Wrba F, Wyatt J, Yamabe H. 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 2000 Mar; 31(3):792–799.

26.Neuberger J. Recurrent primary biliary cirrhosis. Baillieres Best Pract. Res Clin Gastroenterol 2000;14:669–680.

27.Wiesner RH. Liver transplantation for primary sclerosing cholangitis: timing, outcome, impact of inflammatory bowel disease and recurrence of disease. Best Pract Res Clin Gastroenterol 2001;15:667–680.

28.Molmenti EP, Netto GJ, Murray NG, Smith DM, Molmenti H, Crippin JS, Hoover TC, Jung G, Marubashi S, Sanchez EQ,