1 - Front Cover [Seite 1]
2 - Liver Transplantation:Update of Conceptsand Practice [Seite 2]
3 - Copyright [Seite 3]
4 - Contributors [Seite 4]
5 - Contents [Seite 8]
6 - Clinics In Liver Disease [Seite 12]
7 - Preface [Seite 14]
8 - Evolving Trends in Liver Transplantation [Seite 16]
8.1 - Key points [Seite 16]
8.2 - Introduction [Seite 16]
8.3 - History [Seite 16]
8.4 - MELD [Seite 17]
8.5 - Advantages of the MELD score [Seite 18]
8.6 - Disadvantages of the MELD score [Seite 18]
8.7 - MELD exceptions [Seite 19]
8.8 - Evidence-based modifications to the MELD score [Seite 20]
8.9 - Can we improve the MELD allocation policy? [Seite 21]
8.10 - Future changes to liver allocations [Seite 22]
8.11 - Summary [Seite 22]
8.12 - References [Seite 23]
9 - Cardiac and Pulmonary Issues in LT Assessment Candidates [Seite 26]
9.1 - Key points [Seite 26]
9.2 - Introduction [Seite 26]
9.3 - Cardiac issues [Seite 27]
9.3.1 - Preexisting Coronary Artery Disease [Seite 27]
9.3.2 - Cirrhotic Cardiomyopathy [Seite 28]
9.3.3 - Alcohol-Related Cardiomyopathy [Seite 29]
9.3.4 - Posttransplant Metabolic Syndrome [Seite 30]
9.4 - Pulmonary issues [Seite 30]
9.4.1 - Hepatic Hydrothorax [Seite 31]
9.4.2 - Hepatopulmonary Syndrome [Seite 32]
9.4.3 - Portopulmonary Syndrome [Seite 33]
9.4.4 - Hemorrhagic Hereditary Telangiectasia [Seite 35]
9.4.5 - Concomitant Lung Conditions [Seite 37]
9.5 - References [Seite 37]
10 - Renal Dysfunction in End-Stage Liver Disease and Post-Liver Transplant [Seite 40]
10.1 - Key points [Seite 40]
10.2 - Introduction [Seite 40]
10.3 - Patients with cirrhosis and ESLD [Seite 41]
10.3.1 - Revised Definition of Renal Dysfunction in Patients with Liver Disease [Seite 41]
10.3.2 - Estimating Renal Function in Patients with Cirrhosis and ESLD [Seite 41]
10.4 - Types of renal dysfunction [Seite 42]
10.4.1 - Prerenal Azotemia [Seite 42]
10.4.2 - The HRS [Seite 42]
10.4.3 - Intrinsic Renal Disease [Seite 43]
10.5 - Role of RRT [Seite 47]
10.6 - Evaluation for CLKT [Seite 47]
10.7 - Kidney injury in the post-liver transplant period [Seite 47]
10.8 - Summary [Seite 52]
10.9 - References [Seite 52]
11 - Acute-On-Chronic Liver Failure [Seite 58]
11.1 - Key points [Seite 58]
11.2 - Introduction [Seite 58]
11.3 - ACLF is not decompensated cirrhosis [Seite 59]
11.4 - Physiology of ACLF [Seite 59]
11.4.1 - Renal [Seite 61]
11.4.2 - Brain [Seite 62]
11.4.3 - Circulatory [Seite 62]
11.4.4 - Pulmonary [Seite 63]
11.5 - Definitions of ACLF [Seite 64]
11.5.1 - APASL [Seite 64]
11.5.2 - EASL-CLIF [Seite 64]
11.5.3 - NACSELD [Seite 65]
11.5.4 - Regional Differences in Defining ACLF [Seite 65]
11.6 - Predictive models [Seite 66]
11.7 - ACLF in pretransplant patients [Seite 67]
11.8 - Medical therapy [Seite 67]
11.8.1 - Liver Assist Devices [Seite 67]
11.9 - ACLF and outcomes after LT [Seite 68]
11.10 - Unresolved questions [Seite 68]
11.11 - References [Seite 69]
12 - Hepatitis Viruses and Liver Transplantation [Seite 72]
12.1 - Key points [Seite 72]
12.2 - Antiviral management of hepatitis C virus in liver transplant recipients [Seite 73]
12.2.1 - The Diagnosis of HCV Recurrence [Seite 73]
12.2.2 - Antiviral Treatment to Prevent HCV Recurrence [Seite 75]
12.2.2.1 - Treatment on the liver transplant waitlist [Seite 75]
12.2.2.2 - Prophylactic and preemptive HCV treatment [Seite 77]
12.2.3 - Antiviral Therapy for the Treatment of Significant Recurrent HCV [Seite 77]
12.3 - Recent advances in the antiviral management of liver transplant recipients with hepatitis B [Seite 81]
12.3.1 - Antiviral Strategies to Prevent HBV Recurrence [Seite 82]
12.3.1.1 - HBV treatment on the transplant waitlist [Seite 82]
12.3.1.2 - HBV reinfection prevention strategies after liver transplantation and the evolving role of HBIG [Seite 82]
12.3.2 - De Novo Infection and the Use of Hepatitis B Core Antibody-Positive Donors [Seite 84]
12.3.3 - Treatment of Recurrent and De Novo HBV Infection After LT [Seite 84]
12.4 - Hepatitis E virus in liver transplant recipients: an emerging cause of graft dysfunction? [Seite 85]
12.4.1 - The Evolving Epidemiology of HEV [Seite 85]
12.4.2 - HEV in Liver Transplant Recipients [Seite 86]
12.4.3 - Donor-Derived HEV Infection [Seite 89]
12.5 - Summary and recommendations [Seite 90]
12.6 - References [Seite 90]
13 - Liver Transplant for Hepatocellular Cancer [Seite 100]
13.1 - Key points [Seite 100]
13.2 - Very small tumors [Seite 100]
13.3 - Very large tumors [Seite 102]
13.3.1 - Extended Criteria-Tumor Size and Number [Seite 102]
13.3.2 - Downstaging [Seite 103]
13.3.3 - Tumor Biology [Seite 103]
13.4 - Waiting time [Seite 105]
13.5 - Summary [Seite 107]
13.6 - References [Seite 107]
14 - The Adolescent Liver Transplant Patient [Seite 110]
14.1 - Key points [Seite 110]
14.2 - Introduction [Seite 110]
14.3 - Definition of adolescence [Seite 111]
14.4 - Specific issues in adolescence [Seite 111]
14.5 - Indications for transplantation [Seite 111]
14.5.1 - Chronic Liver Failure [Seite 111]
14.5.2 - Biliary Atresia [Seite 112]
14.5.3 - Inherited Metabolic Liver Disease [Seite 112]
14.5.3.1 - a1-Antitrypsin deficiency [Seite 112]
14.5.3.2 - Alagille syndrome [Seite 113]
14.5.4 - Progressive Familial Intrahepatic Cholestasis [Seite 113]
14.5.5 - Tyrosinemia Type I [Seite 113]
14.5.6 - Cystic Fibrosis [Seite 113]
14.5.7 - Wilson Disease [Seite 114]
14.5.7.1 - Autoimmune liver disease types I and II [Seite 114]
14.5.8 - Fibropolycystic Liver Disease [Seite 114]
14.5.9 - Primary Immunodeficiency [Seite 114]
14.5.10 - Timing of Transplantation for Adolescents with Chronic Liver Failure [Seite 114]
14.6 - Acute liver failure [Seite 115]
14.6.1 - Drug-Induced Liver Failure [Seite 115]
14.6.1.1 - Viral hepatitis [Seite 115]
14.7 - Management of adolescents with acute liver failure [Seite 115]
14.8 - Inborn errors of metabolism [Seite 116]
14.8.1 - Crigler-Najjar Type I [Seite 117]
14.8.2 - Primary Hyperoxaluria [Seite 117]
14.9 - Liver tumors [Seite 117]
14.10 - Pretransplant evaluation [Seite 117]
14.10.1 - Renal Function [Seite 117]
14.10.2 - Cardiac Assessment [Seite 117]
14.10.3 - Respiratory Assessment [Seite 117]
14.10.4 - Neuropsychological Assessment [Seite 118]
14.11 - Contraindications for transplantation [Seite 118]
14.12 - Preparation for transplantation [Seite 118]
14.12.1 - Immunization [Seite 118]
14.12.2 - Management of Hepatic Complications [Seite 118]
14.12.3 - Nutritional Support [Seite 118]
14.12.4 - Psychological Preparation [Seite 118]
14.12.5 - Liver Transplant Surgery [Seite 118]
14.12.6 - Post-Transplant Management [Seite 119]
14.12.7 - Survival and Quality of Life [Seite 119]
14.12.7.1 - Nutrition, growth, and endocrine development [Seite 119]
14.12.7.2 - Psychosocial development [Seite 119]
14.12.7.3 - Neurocognitive function [Seite 119]
14.12.7.4 - Quality of life [Seite 120]
14.12.8 - Risk Factors Affecting Survival [Seite 120]
14.12.8.1 - Late technical complications [Seite 120]
14.12.8.2 - Maintaining graft function [Seite 120]
14.12.8.2.1 - Immunosuppression [Seite 120]
14.12.8.2.2 - Acute and chronic rejection [Seite 120]
14.12.8.2.3 - Graft hepatitis [Seite 120]
14.12.8.3 - Recurrent disease [Seite 121]
14.12.8.4 - Adverse effects of immunosuppression [Seite 121]
14.12.8.5 - Renal function [Seite 121]
14.12.8.6 - Diabetes mellitus [Seite 121]
14.12.8.7 - Cardiovascular disease [Seite 121]
14.12.8.8 - Sexual health [Seite 121]
14.12.8.8.1 - Contraception and pregnancy [Seite 121]
14.12.8.8.2 - Sexually transmitted diseases [Seite 122]
14.12.8.9 - Risk-taking behaviors [Seite 122]
14.12.8.10 - Adherence [Seite 122]
14.12.9 - Transition to Adult Care [Seite 122]
14.13 - Summary [Seite 123]
14.14 - References [Seite 123]
15 - Expanded Criteria Donors [Seite 130]
15.1 - Key points [Seite 130]
15.2 - The spectrum of donor quality: ideal, standard, and expanded [Seite 130]
15.2.1 - Donor Risk Factors for Graft Dysfunction [Seite 130]
15.2.1.1 - Older donor age [Seite 130]
15.2.1.2 - Donation after cardiac death status [Seite 132]
15.2.1.3 - Steatosis [Seite 133]
15.2.1.4 - Cold ischemia time [Seite 135]
15.2.2 - Donor Risk Factors for Disease Transmission [Seite 135]
15.2.2.1 - Viral hepatitis B [Seite 135]
15.2.2.1.1 - Hepatitis B core antibody positive donors [Seite 135]
15.2.2.2 - HBsAg+ donors [Seite 136]
15.2.2.3 - Viral hepatitis C [Seite 136]
15.2.2.4 - Human immunodeficiency virus [Seite 137]
15.2.2.5 - Centers for Disease Control and Prevention classification of donors at increased risk for infection transmission [Seite 137]
15.2.2.6 - Cancer [Seite 138]
15.3 - References [Seite 140]
16 - Challenges in Living Donor Liver Transplantation [Seite 148]
16.1 - Key points [Seite 148]
16.2 - Introduction [Seite 148]
16.3 - LDLT for hepatocellular carcinoma [Seite 149]
16.4 - ABO-incompatible LDLT [Seite 151]
16.5 - Donor risk and complications [Seite 152]
16.6 - References [Seite 154]
17 - Multivisceral Transplantation [Seite 158]
17.1 - Key points [Seite 158]
17.2 - Introduction [Seite 158]
17.3 - Intestinal failure [Seite 159]
17.4 - Indications [Seite 159]
17.5 - Contraindications [Seite 161]
17.6 - Types of grafts [Seite 161]
17.6.1 - Isolated Intestinal Transplant [Seite 162]
17.6.2 - Combined Liver-Pancreas-Small Bowel Transplant [Seite 162]
17.6.3 - Multivisceral Transplantation [Seite 162]
17.7 - Surgical technique [Seite 164]
17.8 - Postoperative management [Seite 164]
17.9 - Immunosuppression [Seite 165]
17.9.1 - Nonsurgical Complications [Seite 165]
17.9.1.1 - Rejection [Seite 165]
17.9.1.2 - Graft-versus-host disease [Seite 167]
17.9.1.3 - Posttransplant lymph proliferative disorder [Seite 168]
17.9.1.4 - Cytomegalovirus [Seite 169]
17.10 - Outcomes [Seite 169]
17.11 - Summary [Seite 170]
17.12 - References [Seite 170]
18 - Recurrence of Nonviral Liver Diseases After Liver Transplantation [Seite 172]
18.1 - Key points [Seite 172]
18.2 - Introduction [Seite 172]
18.3 - AIH, PBC, and PSC [Seite 173]
18.3.1 - AIH [Seite 173]
18.3.2 - PBC [Seite 174]
18.3.3 - PSC [Seite 175]
18.4 - ALD [Seite 176]
18.5 - Nonalcoholic fatty liver disease [Seite 177]
18.6 - Other rare indications for LT [Seite 178]
18.7 - Summary [Seite 178]
18.8 - References [Seite 178]
19 - Immunosuppression [Seite 184]
19.1 - Key points [Seite 184]
19.2 - Part I: current immunosuppression practices [Seite 184]
19.3 - Part II: minimization as a goal for transplantation [Seite 188]
19.3.1 - Overview [Seite 188]
19.3.2 - Management of Immunosuppression with the Aim of Decreasing Adverse Effects [Seite 189]
19.3.2.1 - Immunosuppression-induced kidney injury [Seite 189]
19.3.2.2 - Metabolic syndrome [Seite 189]
19.3.2.3 - Malignancy and infections [Seite 190]
19.3.2.4 - HCV recurrence [Seite 190]
19.3.3 - Clinical Observation of Minimization of CNI Immunosuppression in Liver Transplantation [Seite 191]
19.3.4 - Long-term Management of Immunosuppression in Adult Transplant Recipients [Seite 191]
19.3.5 - Minimization in the Pediatric Liver Transplant Setting [Seite 193]
19.3.6 - Feasibility of Immunosuppression Minimization [Seite 194]
19.3.7 - Can IM Be Personalized? [Seite 194]
19.4 - Part III: tolerance [Seite 195]
19.4.1 - Conceptual Approach to the Induction of Donor-Specific Tolerance [Seite 195]
19.4.2 - Clinical and Experimental Approach to the Induction of Donor-Specific Tolerance [Seite 195]
19.4.2.1 - Molecular therapeutics [Seite 195]
19.4.2.2 - Cellular therapeutics [Seite 196]
19.4.3 - Experimental Models of Liver Transplant Tolerance in Animals [Seite 196]
19.4.3.1 - Liver transplant tolerance in humans [Seite 198]
19.4.4 - Lessons from Tolerance in Renal Transplantation and the Quest for Biomarkers [Seite 200]
19.4.5 - Current Clinical Tolerance Trials [Seite 202]
19.5 - Summary [Seite 203]
19.6 - References [Seite 204]
20 - Improving Long-Term Outcomes After Liver Transplantation [Seite 214]
20.1 - Key points [Seite 214]
20.2 - Introduction [Seite 214]
20.3 - Causes of death after LT [Seite 215]
20.4 - The impact of immunosuppression and rejection on outcomes [Seite 216]
20.4.1 - Impact of Acute Cellular Rejection on Overall Patient and Graft Survival Varies with Underlying Liver Disease [Seite 216]
20.4.2 - Immunosuppression in Patients with HCV Infection [Seite 218]
20.4.2.1 - Corticosteroids [Seite 218]
20.4.2.2 - Calcineurin inhibitors [Seite 218]
20.4.2.3 - Mycophenolate mofetil [Seite 218]
20.4.2.4 - T-cell-depleting therapies [Seite 218]
20.4.2.5 - Interleukin-2 receptor inhibition [Seite 219]
20.4.2.6 - Rejection and immunosuppression-related morbidity and mortality in other etiologies of liver disease [Seite 219]
20.5 - Posttransplant MS and long-term mortality and graft loss [Seite 220]
20.6 - Components of MS post-LT [Seite 220]
20.6.1 - Obesity [Seite 220]
20.6.2 - Posttransplant Pharmacotherapy of Obesity [Seite 221]
20.6.3 - Diabetes [Seite 221]
20.6.4 - Dyslipidemia [Seite 222]
20.6.5 - Hypertension [Seite 223]
20.6.6 - Cardiovascular Disease [Seite 223]
20.7 - Malignancy [Seite 223]
20.8 - References [Seite 225]
21 - Hepatic Retransplant [Seite 228]
21.1 - Key points [Seite 228]
21.2 - Why do liver transplants fail? [Seite 230]
21.3 - Should hepatitis C recurrence preclude retransplant? [Seite 232]
21.4 - Liver allocation for hepatic retransplant: the status quo [Seite 233]
21.5 - Can the timing of retransplant predict patient survival? [Seite 235]
21.6 - Which recipient characteristics are associated with worse prognosis? [Seite 236]
21.7 - Better donor grafts, better outcomes [Seite 237]
21.8 - Achieving optimal outcomes after retransplant: the utility of risk prediction models [Seite 237]
21.9 - Technical challenges of hepatic retransplant [Seite 240]
21.10 - Summary [Seite 242]
21.11 - References [Seite 243]
22 - Index [Seite 250]
Evolving Trends in Liver Transplantation
Listing and Liver Donor Allocation
Russell H. Wiesner, MD rwiesner@mayo.edu, Mayo College of Medicine, Rochester, MN 55905, USA
The success of liver transplantation in the past three decades as a life-saving procedure for patients with end-stage liver disease has led to the ever-increasing disparity between the demands for liver transplantation and the supply of donor liver organs. Donor allocation and distribution remains a challenge and a moral issue as to how these organs can be equitably distributed. This article reviews the evolution of the liver allocation policy and discusses in detail the challenges clinicians face today in this area of medicine.
Keywords
Liver transplantation
MELD
Liver donor allocation
Chronic liver disease
Key points
• The MELD-based allocation policy is excellent at prioritizing patients with chronic liver disease on the waiting list based on survival.
• Exception criteria are needed because of such conditions as hepatocellular cancer, with tumor progression being used as a surrogate for patient survival.
• MELD can be tweaked by adding serum sodium and other variables; but overall the impact would be minimal and reprograming is expensive and cumbersome.
Introduction
The success of liver transplantation in the past three decades as a life-saving procedure for patients with end-stage liver disease has led to the ever-increasing disparity between the demands for liver transplantation and the supply of donor liver organs. This demand has been fueled by an increasing prevalence of cirrhosis and hepatocellular cancer (HCC) related to the hepatitis C epidemic, and to the increase in obesity-related liver disease.1 Today, nearly 1 in 10 patients waiting for a donor liver organ die on the waiting list.2 Therefore, donor allocation and distribution remains a challenge and a moral issue as to how these organs can be equitably distributed. This article reviews the evolution of the liver allocation policy and discusses in detail the challenges we face today.
History
Donor liver allocation dates back to the Transplantation Act of 1983 when there were only a few liver transplant centers in the United States. However, with the increasing success of liver transplantation and expanded indications, the number of patients seeking this life-saving procedure continued to grow. At the same time, the number of institutions offering liver transplantation also increased. By the mid-1990s, livers were allocated based on blood type; time on the liver transplant waiting list; and whether a patient was in the intensive care unit (ICU), hospital, or an outpatient. There was no criterion to define which patients should be in the ICU or which patients should be hospitalized. Indeed, many centers admitted patients to the ICU solely to facilitate their placement at the top of the liver waiting list. In retrospect, it was noted in the model for end-stage liver disease (MELD) era that the number of patients proceeding to liver transplantation from the ICU dropped dramatically from 24% in the pre-MELD era to 13% in the post-MELD era.3 There was also noted to be a strong relationship between the number of centers in an organ procurement unit, and the number of patients undergoing liver transplant directly from the ICU.
An attempt to rectify this problem was made in 1998 by implementation of a new system incorporating the Child-Turcotte-Pugh score (CTP) as an index for liver disease severity and prognosis. This scoring system was originally used to predict the outcome of portal-cava shunt surgery in patients with cirrhosis.4 Adoption of the CTP-based allocation system was intended primarily to reflect waiting list mortality and severity of liver disease. However, the use of the CTP score for the prioritization of liver transplant candidates had several major drawbacks. First, ascites and encephalopathy were subjectively assessed and were influenced by such therapies as diuretics, albumin administration, and lactulose therapy. In addition, a score of three points was allocated for any serum bilirubin value higher than 3.0 mg/dL and any serum albumin level value of 2.8 mg/dL or less. This “ceiling and floor affect” for bilirubin and albumin, respectively, meant that many patients ended up with the same overall CTP score, even though they may have had vastly different values of these two variables. Indeed, a patient with a serum bilirubin of 25 mg/dL received the same CTP score as the patient who had a serum bilirubin of 3 mg/dL. As a result, time spent on the waiting list became the major selection factor of liver candidates having identical CTP scores. Finally, there was no parameter in the CTP score that reflected renal function, a key prognostic marker in patients with end-stage cirrhosis. Two studies found time spent on the waiting list was not associated with risk of death on the waiting list.5,6 In the end, the revised allocation policy based on the CTP score ultimately proved unworkable and unfair to patients with the most severe liver disease. Because of considerable disagreement among transplant centers on how livers should be allocated, the United Network for Organ Sharing (UNOS) and the Department of Health and Human Services intervened in 1999 and challenged the transplant community with “The Final Rule.”7 Among the conditions of the Final Rule were that allocation policies should be based on objective and measurable medical criteria of patients or categories of patients who are medically suitable candidates for liver transplantation. In addition, it noted that patients should be rank-ordered according to severity of disease and predicted mortality on the liver waiting list. The Final Rule stipulated that waiting time should be deemphasized, that allocation should be designed to achieve equitable allocation of organs among patients, and that organs should be distributed over as broad a geographic area as feasible in order of decreasing medical urgency. Finally, the Final Rule noted that neither place of residence nor place of listing should be a major determinant of access to a liver transplant. This challenge was ultimately met by the adoption of the MELD score by UNOS in February 2002.
MELD
The MELD score was first used and published in 2000 by Malinchoc and colleagues8 to predict survival in patients undergoing elective transjugular intrahepatic portal-cava systemic shunts. In 2001, the Mayo Clinic group modified the score to predict mortality in a wide range of liver disease etiologies and severities.9 In the final model, cause of liver disease was eliminated from the model and three biochemical variables were used: (1) serum bilirubin, (2) international normalized ratio (INR), and (3) serum creatinine level. Retrospective studies demonstrated that the MELD score had a high degree of discriminative ability in prediction of 3-month survival in patients with cirrhosis, regardless of the cause of liver disease, and was independent of complications of liver disease, such as ascites, encephalopathy, variceal bleeding, and spontaneous bacterial peritonitis.9 The final assessment of the MELD score was made using 3437 patients on the UNOS liver transplant waiting list. In this study the MELD score was found to be superior to the CTP score for predicting 3-month survival.10 The C statistic for predicting 3-month survival on the waiting list was 0.83. This study led to the adoption of the MELD score for liver donor allocation in the United States in February 2002. Since that time, the MELD score has been validated around the world and is presently used in many countries today to allocate donor liver organs.11–13 Indeed, there are more than 1000 papers published in the last decade on the MELD score. The MELD score has been thoroughly scrutinized and a decade later remains the standard by which to predict mortality in patients with end-stage liver disease.
Advantages of the MELD score
Advantages of the MELD score are its statistical validation and the use of objective widely available laboratory tests (serum bilirubin, serum creatinine, and INR of prothrombin). Today several online calculators are available for calculating the MELD score. It initially was thought that the MELD score might prioritize sicker patients who were more likely to die following liver transplantation.
The impact of the MELD allocation policy resulted in a reduction in waiting list registration by 12%, a reduction in death on the waiting list by 5%, decreased median waiting times from 676 to 416 days, and patients transplanted within 30 days of listing increased from 23% in the pre-MELD era to 37% in the post-MELD era.14 In the MELD era although sicker patients were transplanted posttransplant survival actually slightly improved, thus dispelling concerns that many had about reducing death on the waiting list, but increasing death posttransplant.15,16 However, transplantation of sicker patients with higher MELD scores has led to an increase in the cost of liver transplantation and resource...
