Overview of the Indications and Contraindications for Liver Transplantation Stefan Farkas, Christina Hackl, and Hans Ju ¨ rgen Schlitt Department of Surgery, University Medical Center Regensburg, D-93053 Regensburg, Germany Correspondence: [email protected]Liver transplantation is the only definitive treatment option for patients with irrevocable acute or chronic liver failure. In the last four decades, liver transplantation has developed from an experimental approach with a very high mortality to an almost routine procedure with good short- and long-term survival rates. Here, we present an up-to-date overviewof the indica- tions and contraindications for liver transplantation. It is shown how the evaluation of a candidate and finally listing for transplantation has to be performed in a multidisciplinary setting. Meticulous listing, timing, and organ allocation are the crucial factors to achieve an optimal outcome for the individual patient on the one hand, and reasonably using the limited deceased donor pool on the other hand. Living-donor liver transplantation is de- manding but necessarily increasing. Because patients after liver transplantation need lifelong aftercare, it is important for primary care cliniciansto understand the basic medical problems and risks. D espite significant improvements in the medical management of the complications of liver cirrhosis including hepatocellular carci- noma, liver transplantation (LTx) remains the only definitive treatment option for patients with end-stage liver disease. Significantly im- proved graft and patient survival rates have been observed over time and, in the last 15 years, are relatively stable, with an overall survival rate of 85% in the first year and 75% at 5 yr (Kim et al. 2013). However, 10% of patients listed for LTx die on the waiting list (Kim et al. 2006), and many potential candidates are not listed be- cause of the shortage of deceased donor organs (Fig. 1). Other patients are not candidates be- cause of comorbidities, psychosocial issues, and medical issues like hepatocellular carcinoma ex- ceeding a designated size. Acute liver failure is less common but has an excellent outcome if the patient is transplanted promptly. HISTORY The pioneer of human orthotopic liver trans- plantation, Thomas E. Starzl, learned about ex- perimental auxiliary liver transplant models in dogs while attending a lecture by C. Stuart Welch in 1957 (Starzl 2012). After discussing and refining these canine models, Starzl was the first to attempt an orthotopic liver trans- plant into a 3-yr-old human recipient suffering from biliary atresia in 1963 (Starzl et al. 1963). The patient did not survive the operation. After several equally unsuccessful attempts, Starzl Editors: Laurence A. Turka and Kathryn J. Wood Additional Perspectives on Transplantation available at www.perspectivesinmedicine.org Copyright # 2014 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a015602 Cite this article as Cold Spring Harb Perspect Med 2014;4:a015602 1 www.perspectivesinmedicine.org on July 21, 2020 - Published by Cold Spring Harbor Laboratory Press http://perspectivesinmedicine.cshlp.org/ Downloaded from
Transcript
Overview of the Indications andContraindications for Liver Transplantation
Stefan Farkas, Christina Hackl, and Hans Jurgen Schlitt
Department of Surgery, University Medical Center Regensburg, D-93053 Regensburg, Germany
Liver transplantation is the only definitive treatment option for patients with irrevocable acuteor chronic liver failure. In the last four decades, liver transplantation has developed from anexperimental approach with a very high mortality to an almost routine procedure with goodshort- and long-term survival rates. Here, we present an up-to-date overview of the indica-tions and contraindications for liver transplantation. It is shown how the evaluation of acandidate and finally listing for transplantation has to be performed in a multidisciplinarysetting. Meticulous listing, timing, and organ allocation are the crucial factors to achieve anoptimal outcome for the individual patient on the one hand, and reasonably using thelimited deceased donor pool on the other hand. Living-donor liver transplantation is de-manding but necessarily increasing. Because patients after liver transplantation need lifelongaftercare, it is important for primary care clinicians to understand the basic medical problemsand risks.
Despite significant improvements in themedical management of the complications
of liver cirrhosis including hepatocellular carci-noma, liver transplantation (LTx) remains theonly definitive treatment option for patientswith end-stage liver disease. Significantly im-proved graft and patient survival rates havebeen observed over time and, in the last 15 years,are relatively stable, with an overall survival rateof 85% in the first year and �75% at 5 yr (Kimet al. 2013). However, �10% of patients listedfor LTx die on the waiting list (Kim et al. 2006),and many potential candidates are not listed be-cause of the shortage of deceased donor organs(Fig. 1). Other patients are not candidates be-cause of comorbidities, psychosocial issues, andmedical issues like hepatocellular carcinoma ex-
ceeding a designated size. Acute liver failure isless common but has an excellent outcome if thepatient is transplanted promptly.
HISTORY
The pioneer of human orthotopic liver trans-plantation, Thomas E. Starzl, learned about ex-perimental auxiliary liver transplant models indogs while attending a lecture by C. StuartWelch in 1957 (Starzl 2012). After discussingand refining these canine models, Starzl wasthe first to attempt an orthotopic liver trans-plant into a 3-yr-old human recipient sufferingfrom biliary atresia in 1963 (Starzl et al. 1963).The patient did not survive the operation. Afterseveral equally unsuccessful attempts, Starzl
Editors: Laurence A. Turka and Kathryn J. Wood
Additional Perspectives on Transplantation available at www.perspectivesinmedicine.org
Copyright # 2014 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a015602
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succeeded in performing an orthotopic livertransplant into a patient diagnosed with hepa-toblastoma in 1967 (Starzl et al. 1968). Thispatient survived for 18 mo before dying frommetastatic disease. During the following years,major breakthroughs such as the expansion ofthe organ donor pool by introduction of thebrain-dead criteria in 1968 (Shapiro 1968), re-fined surgical technique, and, last but not least,introduction of new immunosuppressive med-ication such as cyclosporine in 1979 (Starzl et al.1981a,b) led to a significant increase in livertransplantation. In 1983, the NIH declaredthat liver transplantation was a valid therapyfor end-stage liver disease (National Institutesof Health 1984), and, a few years subsequently,the United Network for Organ Sharing (UNOS)was founded (United States Congress 1984). Al-ready in 1967, the Eurotransplant (ET) Inter-national Foundation was founded in Leiden,The Netherlands. In 1988, Rudolf Pichlmayrwas the first to perform a split-liver transplan-tation, offering one liver to two recipients(Pichlmayr et al. 1988). In 1988 and 1989, liv-ing-donor liver donation was successfully intro-duced in the adult-to-pediatric and adult-to-adult settings (Fig. 2) (Broelsch et al. 1990).As of today, approximately 6200 and 1700 livertransplants are performed each year within theUNOS and ET networks, respectively.
INDICATIONS FOR LIVERTRANSPLANTATION
Indications for liver transplantation are mani-fold and can be classified into end-stage liver
disease, acute liver failure, and certain benignand malignant liver tumors. An overview is giv-en in Table 1. Liver transplantation should beconsidered for any patient in whom anticipatedoverall survival exceeds life expectancy of theunderlying disease or where a significant in-crease in quality of life can be achieved. Withinthe UNOS and ET networks, liver cirrhosiscaused by chronic viral hepatitis and alcoholabuse is the major cause for end-stage liver dis-ease, accounting for �70% of liver transplanta-tions (Zakhari 2013).
Liver transplantation for malignant diseaseis a medical and ethical challenge with regardto long-term oncological outcome under im-munosuppressive therapy and allocation justicebecause of organ shortage. Childhood hepato-blastoma (Meyers et al. 2012), epitheloid he-mangioendothelioma (Grossman and Millis2010), and limited hepatocellular carcinoma(HCC) (Dhir et al. 2012; Lim et al. 2012), withinthe Milan criteria (one lesion �5 cm, or two tothree lesions each�3 cm, no extrahepatic lesionand no vascular invasion), are standard indica-tions for liver transplantation. Patients diag-nosed with HCC—often presenting in goodclinical condition—therefore receive additionalMELD (model of end-stage liver disease) pointsaccording to HCC tumor size and waiting timeto enable transplantation before the tumor ex-ceeds the Milan criteria (Earl and Chapman2013). Surgical resection and therapeutic inter-ventions to control HCC progress during thewaiting period as well as liver transplantationfor patients exceeding the Milan criteria are a
Figure 1. Liver of a deceased organ donor.
Figure 2. Splitting of liver for two recipients: oneadult and one pediatric.
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focus of ongoing clinical research (Yao 2008).Living-donor liver transplantation may hereoffer a treatment option for selected HCC pa-tients to minimize waiting time or enable livertransplantation in tumors exceeding the Milancriteria (Grant et al. 2013). In contrast, patientsdiagnosed with intrahepatic cholangiocellu-lar adenocarcinoma (CCA) have shown poorlong-term overall survival after liver transplan-tation and are not transplant candidates (Ali etal. 2011). However, recent clinical trials by theMayo Clinic evaluating a multimodality treat-ment concept for CCA combining neoadjuvantradiochemotherapy and liver transplantationhave established CCA as an indication for livertransplantation in selected patients with unre-sectable hilar CCA or CCA arising in patientswith primary sclerosing cholangitis (Rosenet al. 2010; Darwish Murad et al. 2012). Clinicaltrials evaluating liver transplantation for select-ed patients with neuroendocrine hepatic metas-tases have shown long-term graft and patientsurvival comparable with patients transplantedfor HCC (Gedalyet al. 2011). In individual cases,patients with neuroendocrine liver metastasesthus are eligible for liver transplantation. Extra-hepatic malignancies as well as hepatic metas-tases from non-neuroendocrine tumors so farremain absolute contraindications for livertransplantation. However, a recent Norwegianpilot study evaluating liver transplantation forunresectable colorectal liver metastases showedthat overall survival exceeds by far the reportedoutcome for chemotherapy, is comparable withoverall survival after liver resection for resectablecolorectal liver metastases, and is comparablewith overall survival after repeat liver transplan-tation for nonmalignant diseases (Hagness et al.2013). Thus, ongoing improvements in multi-modality cancer therapy may in the futurewidenindications for liver transplantation in malig-nant disease.
CONTRAINDICATIONS FOR LIVERTRANSPLANTATION
Absolute and relative contraindications for livertransplantation are shown in Table 2. Abstinencefrom alcohol and drug abuse for a minimum of
Table 1. Indications for liver transplantation
Acute liver failureHepatitis A/BIntoxication (e.g., acetaminophen, death cap)Wilson’s diseaseBudd–Chiari syndrome
6 mo is required in the UNOS, ET, and othertransplant programs. This mandatory durationof abstinence is a matter of debate because the 6-mo threshold has shown to be insufficient forpredicting long-term graft and patient survival(Rice and Lucey 2013). Although uncontrolledsystemic infections, which exclude patient sur-vival under immunosuppression, and AIDS-de-fining symptoms in HIV patients are absolutecontraindications, the possibility of performinga liver transplantation in patients diagnosedwith infections such as HBV and HIV and con-trollable local infections must be assessed foreach individual patient (Grossi 2003; Tavioet al. 2011; Campsen et al. 2013). Further abso-lute contraindications for liver transplantationare life-limiting medical conditions such as ad-vanced cadiovascular, pulmonary, or neurologicdisorders; intrahepatic CCA; hepatic metastasesother than neuroendocrine metastases in select-ed patients; and extrahepatic malignancy (seealso Lakkis and Lechler 2013).
Patients diagnosed with HCC exceeding theMilan criteria can still be candidates for livertransplantation, depending on local or nationalallocation guidelines (Yao 2008; Grant et al.2013). In cancer survivors with complete remis-sion, a tumor-free survival of 2–5 yr, depend-ing on the type of malignancy, is required beforelisting for liver transplantation (Bachir and Lar-son 2012).
Relative contraindications may be psycho-social conditions resulting in poor compliance,advanced age, and severe hepatopulmonary orhepatorenal syndrome that may not be cured orimproved after liver transplantation, as well as
severe obesity or severe malnutrition. Here, theindication must be assessed individually foreach patient.
EVALUATION
From a transplant-physician viewpoint, pa-tients should be referred for consideration forliver transplantation as early as possible. Refer-ral does not automatically mean listing of thepatient, but allows thorough assessment of can-didacy for transplant before listing. If the inter-disciplinary decision is made that the patient iseventually a candidate for listing, an extensivepatient evaluation is performed (Table 3).
After exclusion of absolute contraindica-tions and discussion of relative contraindica-tions, several medical, psychosocial, and ethicalquestions have to be answered:
† Can the patient survive the operation andpostoperative period?
† What gain of lifetime and what quality of lifewill the patient have after transplantation?
† Will the patient be compliant regarding themedical regimen?
† In patients with alcoholic liver disease and/or a history of drug abuse, besides being ab-stinent for at least 6 mo, what is the chance ofthe patient staying abstinent lifelong?
† Psychosocial issues: Do psychological disor-ders or lack of social support compromiselong-term outcome?
† Is living donation an option?
Some comorbidities are discovered only atthe evaluation process but can also be correctedbefore transplantation. As the transplant patientage has increased throughout the years, cardio-vascular disease is common and has to be treat-ed before listing. An increasing number of pa-tients in Western countries suffer from morbidobesity and have to be critically evaluated con-cerning perioperative risk and probable need ofweight loss with or without bariatric surgery.Up to one-third of patients with cirrhosis de-velop diabetes. These patients require goodmetabolic control before listing because the re-
Table 2. Contraindications for liver transplantation
Absolute
contraindication
Relative
contraindications
Active alcohol abuse Psychosocial conditionsUncontrolled systemic
infectionsAdvanced age
Uncontrolledextrahepaticmalignancy
Severe hepatopulmonaryor severe hepatorenalsyndrome
Uncontrolled/limitingmedical conditions
Severe obesity/malnutrition
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quired immunosuppression itself increases therisk of and probably worsens preexisting diabe-tes mellitus (Prokai et al. 2012).
Portopulmonary hypertension and hepato-pulmonary syndrome may be reversed by livertransplantation. However, uncontrolled porto-pulmonary hypertension during the transplan-tation procedure may cause severe anesthesiaproblems and severe damage to the graft due toelevated central venous pressure.
Hepatorenal syndrome may also be reversedafter transplantation, but a simultaneous listingfor liver and kidney may be considered if persis-tence of chronic kidney disease is suspected (An-geli and Gines 2012). Because the results of asimultaneous liver and kidney transplantationare critical (Papafragkakis et al. 2010), with anincreased loss of kidneys in the Eurotransplantarea, the following solution was found. Patientslisted simultaneously for liver and kidney can befirst transplanted with a liver alone and receiveextra points on the kidney waiting list. If they arestill in need of a kidney transplant (clearanceis ,15 mL/min) 90–360 d after liver transplan-tation, they have the chance to receive a kid-ney transplant within 3 mo. Thus, loss of kidneysduring simultaneous transplantation, earlydeath with a functioning kidney graft, and un-necessarykidney transplantationsshould bepre-vented. This approach hasto be evaluated duringthe next years.
The listing criteria by the UNOS state thatLTx candidates can be listed for kidney trans-plantation too if they have a documented stage4–5 chronic kidney disease, acute kidney injurywith a glomerular filtration rate lower than25 mL/min continuously for 6 wk, or a meta-bolic disease such as hyperoxaluria.
Patients with HCC who are eligible for anexceptional MELD (eMELD) have to be evalu-ated concerning the specificity of the lesion andthe size and number of tumors and vascularinfiltration in the liver. Furthermore, extrahe-patic spread has to be excluded. For that pur-pose, imaging with MRI and CT and—for spe-cificity of the typical arterial hyperperfusion inthe HCC lesion—contrast enhanced ultrasound(CEUS) is recommended. Thus, it can be eval-uated if the patient fits, for example, in the Mi-
Table 3. Evaluation for liver transplantation
General assessmentsPrevious medical/surgical historyPhysical examinationVaccinations: Hepatitis A/B, tetanus, diphtheria,
polioPsychosocial assessment by psychiatristAssessment by hepatologistConsult with transplant surgeon
Blood testsABO and Rhesus blood group, full blood count,
electrolytes, BUN, creatinine, creatinine-clearance,coagulation (INR, APTT, factor II, factor V), liverfunction tests, glucose, ferritine, transferrine,protein electrophoresis, thyroid hormones, tumormarker (AFP, CA19-9, CEA, CA125 in females;PSA in males), isotypes of antibodies (IgA, IgG,IgM, ANA, AMA)
Screening for infections/tumorsMaxillofascial/dental examinationENTexaminationDermatological examinationGynecology/urology examinationGastroscopyColoscopy in patients at risk or .40 yr
Preparation for surgeryPulmonary function test and blood gas analysisEKG and echocardiographyCardiac catheterization in patients at risk or .65 yrAssessment by transplant anesthetist
Radiologic assessmentX ray of paranasal sinusesThoracic and abdominal three-phase angio-CT scanMammography in female patients at risk or .40 yrDuplex-sonography of the liver
Final assessmentInterdisciplinary review by transplant board
lan criteria or the UNOS criteria for listingwith exceptional MELD. These patients shouldbe also evaluated concerning bridging strategiesuntil the expected time of transplantation. Hereinterventional radiologists and oncological liversurgeons should be included.
LISTING AND TIMING ANDALLOCATION OF LTX
Listing
After extensive evaluation, the final listing of thepatient is an interdisciplinary process. In theliver transplantation board, transplant sur-geons, transplant hepatologists, anesthesiolo-gists, radiologists, transplant coordinators, andpsychiatrists should be included. All participatein the decision of listing the patient formally fortransplantation (Dawwas and Gimson 2009).
Timing and Allocation
Timing is crucial for the success of liver trans-plantation. On the one hand, best results areachieved if the patient is not decompensatedand still in a good general condition. On theother hand, the decompensated and sickest pa-tients are the ones who most urgently need trans-plantation—but have theworstoutcome. Owingto organ shortage, different allocation solutionsare in use but are currently intensively discussed.A model for the sickest-first policy, MELD, wasimplemented in the allocation in the UNOS areain 2002 and in the Eurotransplant area in 2007. Itconsists of serum creatinine, international nor-malized ratio (INR), and bilirubin (patient-based allocation). The MELD calculator can befound, for example, on the following website(www.mayoclinic.org/meld/mayomodel6.htm).The MELD was originally developed to predict3-mo survival after transjugular intrahepaticportosystemic shunt replacement (Malinchocet al. 2000; Said et al. 2004). Since implementa-tion of the MELD system, waiting list mortalityhas declined. However, patients with very highlaboratory MELD scores (.35) are normallyICU-bound, on dialysis, and often require vaso-pressor support and artificial ventilation. If these
patients are transplanted and not temporarilydelisted until recovery, the 1-yr mortality isvery high. Studies are ongoing to assess whetherthe addition of parameters that are associatedwith poor patient outcome (serum sodium, re-nal failure, and serum albumin) will improve thepredictive ability of MELD (Biggins et al. 2005;Kim et al. 2008).
“Center-based allocation” is in use especiallyin countries with few transplant programs, forexample, in Australia, the United Kingdom,and Austria. Moreover, it is used parallel to theMELD system for extended criteria donors andfor recipients who are stable but not well repre-sented in the MELD system. The advantage ofcenter-based allocation is that the physicians canmatch the organ to the patient, which results in arelatively good outcome although extended cri-teria organs are used.
“High-urgency allocation” is generally onlypossible in case of acute liver failure (see above)or for retransplantation.
DECEASED-DONOR LIVERTRANSPLANTATION (DDLT)
The deceased-donor pool is limited. Thus, in thelast decade, different strategies have been imple-mented to increase the pool of deceased liverdonation and transplantation. Donation afterbrain death is widely accepted and well estab-lished. Donation after cardiac death (DCD) iswell established, for example, in the UNOSarea, but still controversial in Europe. The resultsafter DCD transplantation are not as good com-pared with donation after brain death; however,it seems to be a feasible source to increase thedonor pool. In addition, older donors are in-creasingly accepted, because in some countriesthe majority of donors are .50 yr. Absolutecontraindications for deceased organ donationare cancer and uncontrolled infections (e.g.,hepatitis). Cardiac arrest, hypotension, high so-dium, and liver steatosis are not absolute contra-indications. Macroscopic evaluation of the liverat time of retrieval (before and after perfusionwith cold storage solution) is very important toassess organ quality. Frozen sections may notalways be available at the donation site and are
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not optimal to evaluate the degree of steatosis.Extension of the donor pool by use of marginalgrafts may result in higher complication ratessuch as early graft failure, biliary complications(ischemic type biliary lesions), and need for re-transplantation (Busuttil and Tanaka 2003).
Another technique to increase the donorpool is split-liver transplantation. Optimalgrafts can be split into an extended right lobefor an adult recipient and a left lateral lobe fora pediatric recipient (Fig. 3). Also, so-called fullsplits (right and full left lobe for two adult recip-ients) are used in some cases (Gundlach et al.2000). These techniques—if used in experi-enced centers—do have good long-term resultsbut are often limited by logistic and thus ische-mic time problems if the split is allocated to twodifferent centers.
LIVING-DONOR LIVER TRANSPLANTATION(LDLT)
Living-donor liver transplantation (LDLT) is anestablished method with increasing numbers
worldwide. In Asian countries, close to 90% ofliver transplantations are from living donors be-cause of social and religious factors. In westerncountries and especially in the UNOS area, somerecent donor deaths led to a decline in LDLTnumbers. The advantage of LDLT is the use ofan optimal healthy donor, minimal ischemictime, elective surgery, and timing of transplan-tation owing to the recipient’s need and medicalstabilityand not to deceased organ availability. Afurther advantage of LDLT is the possibility ofABO-incompatible transplantation (Song et al.2013). However, living donation is not withoutrisk for the healthy donor, and LDLT is surgicallymore demanding than whole-organ transplan-tation. The remaining liver in the donor regen-erates within 3 mo to 90% of its original volume.The donor has a risk of a 30% morbidity and amortality risk of up to 0.8% (Ghobrial et al.2008). Especially, the bile duct system has to beevaluated intraoperatively by cholangiogram,and aberrant bile ducts have to be taken care ofmeticulously (Jeon et al. 2013). In addition, thevenous outflow in the recipient is crucial, and
A
Anatomy of the liver with liver segments
VII
VIV
VIII
IV
II
III
VII
VIV
VIII
VII
VIV
VIII
IV
IV
II
III
II
III
B
Figure 3. Anatomy of the liver with liver segments (seg). (A) Left lateral splitting or living donation of seg II/IIIfor a pediatric recipient. (B) Living donation of the right lobe (seg V, VI, VII, VIII) for an adult recipient.
Liver Transplantation
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branches of the middle vein may have to be re-constructed. Moreover, in adult LDLT, small-for-size syndrome is sometimes a problem.Thus, a precise imaging evaluation with three-phase CT angiography and volume measure-ment of the future liver remnant of the donoras well as of the graft size have to be performedand calculated with the patient body weight. Forall LDLT, careful selection and extensive evalua-tion of the donor are very important (Table 4)(Berg et al. 2007). All ethical, legal, and insur-ance aspects have to be cleared with the author-ities and well documented. Altogether, a riskadjustment for the donor and the recipient hasto be performed multidisciplinarily. The risk ofthe recipient must equal or exceed the risk of thedonor (Thuluvath and Yoo 2004).
LIVER TRANSPLANTATION—TECHNIQUES
The transplant operation itself has been signifi-cantly standardized and optimized during thelast two decades. Nowadays liver transplanta-tion in a stable donor with a standard donororgan is a routine operation and may be per-formed without any blood transfusion and onlyfew plasma replacements. However, the stan-dards developed for liver transplantation afterdeceased donation are different based on surgi-cal training.
First, the native liver has to be explanted viaright angular incision. Here, two different meth-ods are used: replacement of the inferior venacava (IVC) or so-called piggyback, in which theinferior vena cava is preserved. The clamping ofthe IVC needed for resection can decrease bloodpressure and can cause cardiac problems diffi-cult to manage for the anesthetist. Moreover,renal insufficiency may be a problem becauseof clamping of the IVC causing reduced perfu-sion of the kidneys. Recently, in a Cochrane data-base analysis, the piggyback technique versusstandard technique was reviewed, and theyfound two randomized trials with a total of106 patients (Gurusamy et al. 2011b). Warm is-chemic time was shorter in the piggyback meth-od because only one caval anastomosis had to beperformed. However, the proportion of patientswho developed chest complications was signifi-cantly higher with the piggyback method. Therewas no significant difference in postoperativedeath, primary graft nonfunction, complica-tions related to the blood vessels, kidney failure,blood transfusion requirements, or ICU stay orhospital stay between the two groups. In ourinstitution, we prefer replacement of the IVCbecause we see a substantial shortening of oper-ation time.
To reduce the effects of clamping, the IVCand also the portal vein—which may cause mes-enterial congestion—veno-venous bypass wasonce widely used and has now developed a re-vival in some centers. There are different tech-niques described for the bypass: open or percu-taneous, heparin-coated or no heparin-coated.This was reviewed as well in a Cochrane databaseanalysis, and no difference regarding renal fail-ure or blood transfusions was found between thegroups in two randomized trials (Gurusamyet al. 2011a). The operating time was signifi-cantly shorter in the percutaneous bypass group.To aim at a short operating time, we perform noveno-venous bypass at all at our center.
Another point of discussion is the techniqueof flushing and reperfusion for liver transplan-tation. Marginal organs are prone to ischemictime biliary lesions (ITBL) due to reduced flowin the pericanalicular arteries of the bile ducts.Here some studies hint that the way and se-
Table 4. Supplemental evaluation of the donor forliving donor liver transplantation
Blood testsFibrinogen, AT III, protein C, protein S, factors VII
and VIII, CRP, triglycerides, cholesterol, LDL, HDL
quence of reperfusion influence the rate of ITBL(Heidenhain et al. 2006; Farid et al. 2011). TheCochrane database analysis searched for com-parisons that included initial hepatic arteryflush versus initial portal vein flush or simulta-neous flushing and different types of bloodventing or use of perfusion fluid (Gurusamyet al. 2012). There was no significant differencein mortality, graft survival, or severe morbidityrates in any of the comparisons.
Bile duct reconstruction can be performedwith a duct-to-duct or duct-to-small-bowelanastomosis. Duct-to-small-bowel is recom-mended for patients with PSC. Placing a T-tube or not in the bile duct remains controversial(Gastaca et al. 2013). The bile duct system andthe common bile duct remain the Achilles heelof transplantation, because they are most sensi-tive to early ischemic injury already during coldstorage. We developed a histological bile ductrisk score that predicts biliary complicationsand may help decision making in LTx (Brunneret al. 2013).
POSTTRANSPLANT CARE
Lifelong aftercare is crucial for long-term graftand patient survival after liver transplantation.During the early postoperative phase, dailyblood tests are necessary for surveillance of liverfunction, coagulation, electrolytes, and targetblood levels of immunosuppressive drugs. Fac-tor VII, being produced by the liver and havinga half-life of 6 h, is an excellent parameter toassess liver function on a daily basis. Prophy-lactic antibiotic therapy is given for 3 d peri-operatively. Prophylactic treatment for CMVand PCP infections should be given accordingto the donor/recipient risk profile (Lauten-schlager 2009). Regular duplex-sonography isperformed to assess liver perfusion.
Daily immunosuppressive therapy is man-datory to prevent organ rejection. Especially inthe early posttransplant phase, immunosup-pressive therapy consists of complex combina-tions of various drugs and needs to be adaptedfor each patient individually. Componentsare antilymphocyte antibodies, steroids, calci-neurin inhibitors, and inhibitors of B- and T-
cell proliferation (Scherer et al. 2007). Standardimmunosuppressive combination regimens arebasiliximab, MMF, cyclosporine, and predniso-lone or basiliximab, MMF, sirolimus/everoli-mus, and prednisolone (Farkas et al. 2009).The chimeric monoclonal T-cell IL-2-receptorantibody basiliximab is given on d 0 and 4 afterliver transplant for induction therapy. Myco-phenolate mofetil (MMF), a reversible inhibitorof inosine monophosphate dehydrogenase inpurine synthesis, reduces proliferation of B andT cells (Schlitt et al. 2013). Calcineurin inhibi-tors such as cyclosporine inhibit T-cell produc-tion and excretion of IL-2. mTor inhibitors suchas sirolimus and everolimus also inhibit the pro-liferation of B and T cells. However, in contrastto calcineurin inhibitors, mTor inhibitors showno renal toxicity (Schnitzbauer et al. 2010). Themain side effects are bone marrow toxicity, in-hibition of wound healing, and reduction of liv-er function. On the other hand, mTor inhibitorslower cancer risk in selected patients and there-fore are recommended especially for patientstransplanted for malignant disease (Law 2005).Steroids inhibit T-cell activation and block IL-1and IL-2 synthesis. Steroids are the backbone ofall immunosuppressive regimens and are givenalready before reperfusion of the transplantedorgan intraoperatively. In the early postopera-tive phase, steroids are given in high doses butshould be gradually reduced. In many patients,steroids can be tapered 6 mo after transplanta-tion (Shapiro 2004), and long-term immuno-suppressive therapy often can consist of mono-therapy. Because immunosuppressive drugs caninteract with many other medications and die-tary components, target levels must be checkedlifelong on a regular basis, and interactions mustbe considered when new medications must beintroduced.
Although patients must be closely moni-tored by their transplant center in the early post-operative phase, long-term lifelong aftercare canalso, at least in part, be conducted by generalpractitioners and primary care hospitals. Themain focuses of aftercare must be screening forcomplications and side effects of immunosup-pressive therapy, recognition and treatment ofacute or chronic graft rejection, recognition
Liver Transplantation
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and treatment of biliary complications, malig-nant disease, and recurrence of the primary liverdisease. Details are shown in Table 2. Especially,prevention, recognition, and treatment of infec-tions including opportunistic infections are cru-cial for long-term patient survival because pa-tients under immunosuppressive therapy oftendo not show typical clinical symptoms or leuko-cytosis. Infections can worsen rapidly to septicconditions, and infections present the leadingcause of mortality after liver transplantation(Fishman and Rubin 1998; Torbenson et al.1998).
For prevention of malignant disease, pa-tients must be advised to use high sun-pro-tection-factor sunscreen and to quit cigarettesmoking. Furthermore, preventive screening ex-aminations should be performed on a frequentbasis (see Table 5) (Watt et al. 2009; Chak andSaab 2010). In patients transplanted for hepati-
tis B/C, PBC, PSC, autoimmune hepatitis, andhemochromatosis, screening for disease recur-rence must be performed. Administration ofhepatitis B immune globulin during transplantsurgery and at regular intervals, in combina-tion with antiviral therapy, can prevent HBCrecurrence (Cholongitas et al. 2011). In contrast,treatment with pegylated interferone mono-therapy or combined with ribavirin, owing toliver toxicity, is not started until HCVrecurrenceis proven (Gurusamy et al. 2010). Patients trans-planted for alcoholic liver disease must stay so-ber after liver transplantation, and also patientstransplanted for other indications should ceasealcohol consumption.
FUTURE PERSPECTIVES OF LIVERTRANSPLANTATION
The scarcity of deceased donor organs will re-main one of the main problems for patients onthe waiting list for liver transplantation. In ad-dition, patients with end-stage liver disease areaffected who cannot enter the waiting list at allbecause of strict allocation rules made to coun-terbalance the lack of organs. Extension of thedeceased donor pool is essential but will reacha limit. Living-donation liver transplantation,which is standard procedure in Asian countries,will have to increase also in Western countries tocover the need for lifesaving organs.
Future immunosuppressive strategies in liv-er transplantation have to imply three maingoals:
† Reduction of side effects like renal insufficiency,
† reduction of cancer recurrence of hepatocel-lular carcinoma and de novo cancer aftertransplantation, and
† finally, and optimally, induction of tolerance.
For that purpose, mTOR inhibitors are veryinteresting because they block the central path-way for vital aspects of tumor development, in-cluding angiogenesis and cell growth. mTORinhibitors have anticancer activities, whichmay prove critical in the fight against high can-cer recurrence and de novo cancer. They fur-thermore provide the capacity to interfere
Table 5. Overview of posttransplant aftercare
General assessmentsPhysical examinationDental examinationVaccinations: influenza, pneumonia, hepatitis A/B;
live virus vaccinations should be avoided.
Screening for nonmalignant disease andimmunosuppressant side effects
with fibrotic processes that often accompanytransplant rejection and to influence the prefer-ential development of immunological toler-ance. Studies are ongoing that try to inducetolerance by either stem cell therapy (Dahlkeet al. 2009; Dillmann et al. 2012) or by transfu-sion of regulating cells in the setting of livingdonation (www.onestudy.org).
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