Liver Transplantation - part 10 pps

110 Liver Transplantation 10 advantages for pediatric recipients. The pediatric advantages were granted in re- sponse to concern that the small number of children waiting for liver transplant would be overwhelmed by the huge number of adults with equivalent higher scores, causing increases in deaths and lengthy waiting times. Lengthy waiting time has a disproportionate negative effect on young infants and children due to the impact of chronic liver disease on physical, cognitive and social development. For these reasons, pediatric donors (donors under 18 years of age) are offered to pediatric recipients at an equivalent status or score before potential adult recipients. Furthermore, standard UNOS exceptions exist for specific metabolic diseases, and additional exceptions may be granted by the regional review boards of UNOS on request. Pre-Operative Management • Medical therapy to correct metabolic abnormalities, coagulopathy, ascites, vitamin Deficiencies and malnutrition as much as is possible is a critical part of the management of any child with liver disease. • Malnutrition requires special attention as optimization of nutrition protects brain development prior to transplant and also improves outcome after surgery. Nutritional support can start with institution of a high-density caloric diet, but often infants and young children require supplemental tube feedings. The choice of formula is important, a partially hydrolyzed protein formula with increased medium-chain triglycerides is generally selected to optimize absorption in the face of cholestasis. • Meticulous attention to the delivery of normal “well-child” care is crucial. • Vaccination: children awaiting liver transplantation should receive all standard immunizations (Polio, DPT, HIB, HBV, MMR, Varicella) with particular attention given to live virus vaccines (which are generally not administered to immunosuppressed individuals). Furthermore, additional vaccinations (pneumococcus, influenza, etc.) are generally indicated. Serologic evaluation for prior virus infections (particularly varicella, CMV and EBV) are also of great importance and have considerable impact on post-transplant management and monitoring. Surgical Issues and Options • In the early era of liver transplantation the severe shortage of size-matched donors for infants and young children limited the application of transplantation to pediatric patients. Although the death rate on the waiting list remains significant for children, the risk of dying whilst waiting for a liver allograft has considerably improved for pediatric patients as shown in data in Table 2. • Innovative surgical techniques including reduced-size liver grafts, split and living related grafts has resulted in dramatic improvements in organ procurement for even very small infants and waiting times and deaths have been proportionately reduced. The surgical aspects of these forms of transplant operation are discussed in Chapter 5. • Biliary atresia 111 Pediatric Liver Transplantation 10 - Biliary atresia is the result of an inflammatory/obliterative process of the extrahepatic bile ducts of unknown etiology. Left untreated, this process results in obstructive cholestasis, biliary cirrhosis and death in 100% of children by age 2 years. Management with the Kasai procedure can re- store bile flow in up to 80% of cases with the anastamosis of a bowel limb to the hepatic capsule. Despite the improvement in survival following the Kasai procedure, many of these children will develop complications of portal hypertension in late childhood or adolescence (variceal hemorrhage, ascites) and require transplantation at that time. - Biliary atresia is the most frequent underlying diagnosis in pediatric liver transplant recipients (See Table 1). - Since almost all of candidates undergoing liver transplantation for bil- iary atresia will have had a prior portoenterostomy, the biliary anastamosis is made to the existing or newly revised intestinal “Roux-en-Y” limb rather than to the native common duct (by definition absent in biliary atresia). • Even children with intact extrahepatic biliary structures may require im- plantation of the bile duct into a Roux limb due to size limitations or multiple donor ducts in a partial graft. Use of a Roux limb is an impor- tant feature, as future biliary problems can not be approached by ERCP. Direct visualization of the biliary system can only be achieved by percuta- neous transhepatic cholangiogram in these patients. • Children may require vascular grafts or microsurgical techniques for the vascular anastamoses and the risks of thrombosis (particularly of the he- patic artery) are greatly increased for small infants. Vascular bypass is gen- erally not required for children or infants and is rarely performed (then only in larger teenagers). Early Post-Operative Management The immediate post-operative management of pediatric liver graft recipients is directed toward continued support of liver function, critical care issues and detec- tion of early surgical complications. • Vascular problems: small children and infants are particularly at risk for vascular thromboses so the routine includes frequent Doppler ultrasound to evaluate flow. Pediatric recipients are routinely treated with intrave- nous Dextran to prevent thromboses in the peri-operative period and Table 2. Deaths awaiting OLT in 1990, 1995 and 1999 Age of candidate: < 1 year 1-5 years 6-10 years 11-17 years 1990 268/34/540 265/17/197 100/7/212 161/18/455 1995 337/45/359 389/23/132 208/5/51.6 287/14/110 1999 548/54/234 425/22/92 254/7/48 454/22/80 Data are shown as Patients listed/Deaths/Death rate per 1000 patient years at risk. (Adapted from the UNOS web-site: www.unos.org) 112 Liver Transplantation 10 then receive oral aspirin for 1 year after transplantation. • Bile leaks: Reduced size, living related or split liver grafts have increased risk of bile leak and/or bleeding from the cut surface. • Nutrition: Feeding can be difficult in small children and infants with midline liver placement and short term trans-pyloric tube feeding may be needed. • Immunosuppression: in general immunosuppressive management is similar to that in adults, although the arguments for restricting corticosteroids is even greater. Drug dosages need be considered for the child’s weight. Subsequent Management This is similar to that of adult recipients in terms of monitoring for and management of changes in liver function, rejection, late biliary complications and infections, but there are a few important exceptions. • Nutrition is again of utmost importance in recovery and rehabilitation, though a standard formula can generally replace the specialized feedings used pre-transplant. Very young children and infants who received tube feedings pre-transplant often have delayed oral-motor development and may require feeding therapy in order to accept oral feedings. • Occupational or physical therapy may be necessary for children and infants with a lifetime history of chronic liver disease. Older children generally recover very quickly and are eager to return to school and normal activities, often much faster than their adult counterparts return to work. • Infections: Prophylaxis and surveillance for viral infections, particularly in those young children who did not have primary infections with EBV and CMV pre-transplant, is an ongoing issue. - EBV naïve children undergoing liver transplant are at high risk of devel- oping chronic EBV infection and post transplant lymphoproliferative dis- ease if the primary EBV infection occurs on immunosuppression. The use of new quantitative PCR analysis for EBV has improved the monitor- ing for EBV activity. PTLD is discussed in Chapter 7. In addition to the standard reduction or elimination of immune suppression and addition of ganciclovir or acyclovir antiviral therapy. - CMV negative children will often receive CMV positive grafts (espe- cially if they receive a partial graft from an adult donor) and are at risk of CMV infection. - Exposure to other childhood viral illnesses is an ongoing issue for these children; varicella exposure for example is a frequent occurrence. Chil- dren should be vaccinated for varicella prior to transplant, however the vaccine is less effective if given under 1 year of age. Varicella antibody negative children should receive varicella immune globulin within 48 hours of known exposure (ideally within 12-24 hours) and are treated with intravenous acyclovir if clinical chicken pox develops. Even after an episode of clinical infection most of these children will not develop anti- 113 Pediatric Liver Transplantation 10 bodies and they are therefore at risk for repeated infection with subse- quent exposures. - Live vaccine administration to immunosuppressed transplant recipients is controversial, with standard recommendations against immunization. Even in those centers where MMR and/or varicella immunizations are given post transplant, reduced response to vaccination is observed. • Compliance: Compliance with medical therapy is a major issue with teen- age liver graft recipients especially those transplanted in infancy or early childhood. Many of these teenagers do not remember their transplant experience and are entering a time of personality turbulence, testing of limits, and have acquired a general sense of invulnerability that extends from the usual adolescent risk taking (experimentation with drugs of abuse, exploration of sexuality) to failure to take medications. The response to this behavior must be tailored to the individual child and family and must take into account the social and cultural background. Parents, social workers, school guidance counselors and other resources are important partners in the effort to sustain delivery of medical care through adolescence. The adolescent patient: Children entering adolescence experience a variety of endocrinologic, physical and psychosocial changes. In most cases these young adults will be best served at a pediatric center but care should be transitioned to an adult transplant center when medically and psychosocially appropriate. Suggested Reading 1. Kogan-Liberman D, EMRe S, Shneider BL. Recent advances in pediatric liver transplantation. Current Gastro Reports 2002; 4(1):84-97. 2. Emre S. Living-donor liver transplantation in children. Pediatric Transplantation 2002; 6(1):43-46. 3. Bucuvalas JC, Ryckman FC. Long-term outcome after liver transplantation in chil- dren. Pediatric Transplantation 2002; 6(1):30-36. 4. Shneider BL. Pediatric liver transplantation in metabolic disease: Clinical decision making. Pediatric Transplantation 2002; 6(1):25-29. 5. McDiarmid SV. Management of the pediatric liver transplant patient. Liver Trans- plantation 2001; 7(11suppl 1):S77-S86. 6. Emond JC, Whitington PF, Thistlewaite JR et al. Transplantation of two patients with one liver: analysis of a preliminary experience with “split-liver” grafting. An- nals of Surgery 1990; 212(1):14-22. 7. McDiarmid SV, Gornbein JA, Desilva PJ et al. Factors affecting growth after pedi- atric liver transplantation. Transplantation 1999; 67(3):404-411. 8. Gloss JA, Shackleton CR, McDiarmid SV et al. Long-term results of pediatric liver transplantation: An analysis of 569 patients. Annals of Surgery 1998; 228(3):411-420. 114 Liver Transplantation Index A Acetaminophen 30-33 Acne 67, 102 Acute cellular rejection (ACR) 5, 8, 11, 12, 14, 16, 47, 60, 71, 74-77, 86, 104 Acyclovir 63, 79, 81, 101, 112 Addiction 28, 29, 41, 92, 103 Alcoholism 27, 29, 41, 92, 99 Alloimmune response 5, 7, 9 Alpha feto protein (AFP) 25, 39 Alpha-1-antitrypsin deficiency 108, 109 Amyloidosis 90, 91 Anergy 12-15 Angina pectoris 22 Angiotensin converting enzyme (ACE) 63, 96 Angiotensin II 96 Antibody dependent cellular cytotoxic- ity (ADCC) 13 Antigen presenting cells 5, 15 Apoptosis 11, 14, 15, 64 Argon beam coagulatorargon beam coagulator 54 Autoimmune hepatitis 28, 34, 64, 78, 89, 93, 98 Azathioprine (AZA) 12, 13, 61, 63, 68, 72, 79, 90 B B-cells 5-8, 11, 12, 14 Basiliximab 12, 71 Biliary atresia 4, 109, 110, 111 Biliary cast syndrome 83, 84 Biliary leaks 74, 83, 84 Bone densitometry 27 Breast feeding 72, 104 Burkholderia cepacia 23 C Calcineurin 12, 63, 64, 66, 68, 69, 72, 86, 95-98, 102, 103 Calcium 27, 64, 96, 97, 99, 103 CBD 44, 45, 50, 53 CD antigen 14 CD28 9, 15 CD3 8, 9, 12, 14, 68 Celiac sprue 28, 34 Central pontine myelinolysis 38, 103 Cerebral edema 29, 32 Cervical cancer 100 Cervical carcinoma 101 Chemoembolization 39 Chemokine 10, 15 Child-Pugh classification 17, 18 Cholangiocarcinoma 20, 26, 33, 39, 92 Cholangiogram 57, 59, 111 Cholestipol 20 Cholestyramine 20, 27, 63 Chronic ductopenic rejection (COPD) 11, 12, 15, 22, 34, 71, 74, 76-79, 84 Chronic obstructive pulmonary disease 22 Ciprofloxacin 38 Cirrhosis 3, 4, 18, 19, 27, 30, 33, 34, 36, 39, 41, 79, 86-88, 90, 93, 98, 107-109, 111 Co-amoxyclav 38 Co-stimulation 7 Coagulopathy 19, 29, 37, 74, 103, 110 Colon cancer 26, 33, 39, 101 Common bile duct 44, 50, 53, 57 Complement 11, 13 Cotrimoxazole 38 Creatinine 18, 24, 33, 38, 57, 67, 98 Crigler-Najjar syndrome 90, 107, 109 Cryoglobulinemia 98 Cryotherapy 39 Cryptogenic cirrhosis 34, 93, 109 CSA 13 CTLA-4 15, 63 Cutaneous warts 102 Cyclosporin 12, 13, 63-69, 71, 72, 76, 97, 99, 101-103 Cyclosporine 69 Cystic duct 49, 53, 57 Cystic fibrosis 23, 90, 107-109 Cytokine 7, 9-12, 15, 64, 66, 68 Cytomegalovirus (CMV) 27, 30, 40, 68, 72, 74, 76, 78, 79, 82, 86, 101, 110, 112 Cytotoxic T lymphocyte CTL) 14, 15 115 Index Index D Daclizumab 12, 71 Deletion 12, 13 DEXA scan 99 Diabetes insipidus 42 Diabetes mellitus 25, 65, 67, 72, 95, 97, 98, 104 Diltiazem 66, 96 Direct antigen recognition 8 Diuretics 23, 24, 38, 97 E Ebstein-Barr virus 27 EBV 27, 40, 73, 74, 79, 80, 81, 100, 101, 110, 112 Etidronate 27 Extended criteria donors 46 Extended use organs 2 Extracorporeal perfusion 32 F Factor V 32 FAH 109 Fas 11 Fibrosing cholestatic hepatitis 86 FK506 13 FK506 binding protein 13 FKBP 13, 66 Foscarnet 79 Fulminant hepatic failure 20, 29-33, 34, 79, 109 Fumarylacetoacetate hydrolase 109 G Gadolinium angiography 28 Gallbladder 44, 53, 54, 57, 59 Ganciclovir 79, 81, 112 Gentamicin 38, 66, 72 Glomerulonephritis 72, 98 Glucocorticoids 12, 63, 64 Glypressin 23 Graft versus host disease (GVHD) 15 Granzymes 11 Gum hypertrophy 64, 102 H Halothane 30, 32, 33 Headache 64-68, 103 Hemochromatosis 33, 90, 91 Hemochromatosis gene test 33 Hemorrhagic necrosis 34, 74 Heparin 44, 46 Hepatic artery stenosis 83 Hepatic artery thrombosis (HAT) 34, 69, 74, 79, 81-83 Hepatic osteodystrophy 20 Hepatitis A virus (HAV) 32, 41, 88 Hepatitis B immunoglobulin (HBIg) 33, 88 Hepatitis B virus (HBV) 32, 33, 41, 72, 74, 87, 88, 110 Hepatitis C virus (HCV) 2, 23, 30, 33, 39, 41, 72, 74, 86, 87, 89, 93, 97, 98, 102 Hepatitis D virus (HDV) 33, 78, 88, 93 Hepatoblastomas 26 Hepatocellular cancer 20, 21, 109 Hepatopulmonary syndrome 19, 23, 34 Herpes simplex virus 27 Heterotopic auxiliary transplants 32 HFE 33 HHV-8 100 Hirsutism 64, 102 HMG CoA-reductase inhibitors 97 HPV 100, 101 HPV-6 101 HSV 27, 41, 74 Human herpes virus-8 100 Human immunodeficiency virus (HIV) 20, 26, 42, 57, 100 Human papilloma virus 100 Hydrocortisone 46, 62 Hyperacute rejection 2, 11 Hyperhomocysteinemia 95 Hyperkalemia 64, 97 Hyperlipidemia 34, 67, 69, 95, 97 Hypertension 18, 20, 22, 23, 36-38, 41, 42, 63-65, 67, 68, 83, 95-98, 103, 104, 107, 111 Hypoalbuminemia 24 Hypomagnesemia 97, 103 116 Liver Transplantation Index Hyponatremia 38 I IBD 33 Immunoglobulin superfamily 11 Impotence 25 Inflammatory bowel disease 33 Innate immunity 16 Insomnia 63, 102 Insulin resistance 25, 34, 97 Integrins 11 Interferon 87 Interleukin-2 (IL-2) 7, 9, 12, 64, 66, 67, 71, 79 Interleukin-4 (IL-4) 7, 9, 66 Interleukin-6 (IL-6) 7, 9 Ischemic hepatitis 30 Isoniazid 26, 30, 72, 101 K Kasai procedure 111 Kidney transplantation 24 L Lamivudine 33, 88, 93 Lassitude 102 Lethargy 19 Live donor right lobe recipient operation 59 Live liver donation 20, 21 Living donation 2, 57 Lymphoma 30, 73, 80, 81 M Macrophages 5-7, 10, 11, 14 Magnetic resonance (MR) 25, 28, 33, 39, 41, 57, 82, 83, 89, 93, 103, 110, 113 Major histocompatibility complex (MHC) 5-9, 11, 13-16, 86 Malabsorption 27, 28 Mammography 26, 39 Marginal donors 2 MELD score 17, 18 Menstruation 25 Midodrine 23 Molecular mimicry 8 Musculoskeletal pain 102, 103 Mycophenolate 12, 13, 68, 72, 97 Mycophenolate mofetil 12, 13, 97 Myocardial infarction 22 N Nadalol 36 Naltrexone 20 NASH 34, 74, 93 Nephrotic syndrome 24 Neuroendocrine tumors 26, 93 Niemann-Pick disease 90 Nifedipine 96 NK cells 11 Non-alcoholic fatty liver disorder (NAFLD) 34, 93 Non-alcoholic steatohepatitis 34 Non-heart beating donors 2, 42, 84 Non-heart-beating donors 46 Non-steroidal anti-inflammatory agents 38 Norfloxacin 38 O Obesity 34, 95, 97 OKT-3 12 Oral cancer 100 Ornithine transcarbamylase deficiency 107, 109 Orthoclone 14 Osteopenia 36, 99 Osteoporosis 65, 99, 103 P Palmidronate 27 Pancreatitis 28, 34, 63, 92 Pap smears 39 Parvovirus B19 101 PELD 20, 109 Perforins 11 Peritonitis 19, 36, 37 Phenytoin 20, 32, 66 Plasmapheresis 20 Porcine endogenous retrovirus (PERVs) 2 Portal hypertension 18, 23, 36-38, 83, 107, 111 117 Index Index Portal vein thrombosis 36, 55, 83 Portal venous bypass 50 Porto-pulmonary hypertension 22, 23 Post-transplant lymphoproliferative disorders (PTLD) 80, 100, 112 PPD 26 Pregnancy 30, 67, 68, 72, 104 Primary biliary cirrhosis 18, 19, 34, 79, 88, 98 Primary graft non-function 2, 74 Primary hyperoxaluria 109 Primary sclerosing cholangitis 19, 33, 34, 79, 89, 109 Propranolol 36 Prostatic specific antigen 26, 40 Protoporphyria 90 PSA 26, 40 Psychological assessment 28 Purified protein derivative 26 R Radiofrequency ablation 39 Rapamycin 12, 63, 66, 69 Renal function 23, 24, 28, 57, 97, 98 Retransplantation 3, 4, 34, 35, 54, 72, 76, 83, 84, 86 Ribavirin 87 Rifampicin 65, 66, 101 Rifampin 20 Right lobe living donor operation 57 Roux-en-Y hepatico-jejunostomy 55 S Seizures 68, 103 Selectins 11 Sirolimus 12, 63, 66, 67, 69-72, 97 Skin cancer 20, 80, 97, 100 Somatostatin 23 Split liver grafts 47, 112 Spontaneous bacterial peritonitis (SBP) 19, 36, 37, 38 Statins 66, 97 Steatosis 57 Stent thrombosis 37 Steroid resistant rejection 76 Subacute hepatic necrosis 31 Subfulminant hepatic failure 29, 30 Suppression 3, 12, 16, 20, 60, 61, 63, 66, 68, 70-73, 76, 78, 79, 81, 86, 89, 90, 95, 97, 101, 104, 112 T T helper 7, 14-16 T-cell receptor 5-9 T-cells 5-8, 11-13 T-tube 53, 83, 84 Tacrolimus 12, 13, 63-67, 71-73, 76, 89, 97, 99, 101-103 Target of rapamycin (TOR) 63, 66 TCR 8, 14, 15, 16 Th lymphocytes 7 Th1 and Th2 paradigm 7 Th2 paradigm 7 Thyroid disease 25 Tobacco products 23 Tolerance 7, 12, 14, 16, 30, 60, 87, 104 Transjugular intrahepatic porto- systemic shunt (TIPS) 23, 37, 56, 57 Tr emor 63, 64, 66, 67, 103 Trimethoprim 38 Tuberculosis 26, 72, 101 Ty rosinemia 30, 90, 108, 109 U Ulcerative colitis 26, 39 UNOS 20, 25, 108-110 Ursodeoxycholic acid 20, 89 V Vaccinations 40, 101, 103, 110 Vanishing bile duct syndrome 12, 71, 76 Variceal hemorrhage 19, 36, 37, 41, 111 Varicella zoster 101 Verapamil 66, 96 Vertebral fractures 99 Vitamin A 27 Vitamin D 27, 99, 110 Vitamin K 27 VZV 74, 101 X Xenotransplants 2 V m Michael R. Lucey James Neuberger Abraham Shaked a d e m e c u V a d e m e c u m Table of contents 1. Liver Transplantation: An Overview 2. The Allograft Immune Response 3. Assessment for Liver Transplantation 4. Management on the Liver Transplant Waiting List 5. The Liver Transplant Operation 6. Immunosuppression after Liver Transplantation 7. Graft Dysfunction 8. Recurrence of Disease after Liver Transplantation The Vademecum series includes subjects generally not covered in other handbook series, especially many technology-driven topics that reflect the increasing influence of technology in clinical medicine. The name chosen for this comprehensive medical handbook series is Vademecum, a Latin word that roughly means “to carry along”. In the Middle Ages, traveling clerics carried pocket-sized books, excerpts of the carefully transcribed canons, known as Vademecum. In the 19th century a medical publisher in Germany, Samuel Karger, called a series of portable medical books Vademecum. The Landes Bioscience Vademecum books are intended to be used both in the training of physicians and the care of patients, by medical students, medical house staff and practicing physicians. We hope you will find them a valuable resource. All titles available at www.landesbioscience.com LANDES BIOSCIENCE ISBN 1- 57059- 682- 4 9 781570 596827 LANDES BIOSCIENCE Liver Transplantation 9. Medical Management of the Liver Transplant Patient 10. Pediatric Liver Transplantation . 68, 7 0-7 3, 76, 78, 79, 81, 86, 89, 90, 95, 97, 101 , 104 , 112 T T helper 7, 1 4-1 6 T-cell receptor 5-9 T-cells 5-8 , 1 1-1 3 T-tube 53, 83, 84 Tacrolimus 12, 13, 6 3-6 7, 7 1-7 3, 76, 89, 97, 99, 10 1-1 03 Target. 32 HFE 33 HHV-8 100 Hirsutism 64, 102 HMG CoA-reductase inhibitors 97 HPV 100 , 101 HPV-6 101 HSV 27, 41, 74 Human herpes virus-8 100 Human immunodeficiency virus (HIV) 20, 26, 42, 57, 100 Human. 93, 109 CSA 13 CTLA-4 15, 63 Cutaneous warts 102 Cyclosporin 12, 13, 6 3-6 9, 71, 72, 76, 97, 99, 10 1-1 03 Cyclosporine 69 Cystic duct 49, 53, 57 Cystic fibrosis 23, 90, 10 7-1 09 Cytokine 7, 9-1 2,